Chapter 18 Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia

SECTION V • SPASTIC PARAPLEGIAS

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Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia MARTHA A. NANCE

Introduction The era of gene identification began in the mid-1980s and shows no sign of slowing down. In the research laboratory, the identification of a gene that causes a disease permits the creation of useful laboratory models of the disorder, thereby allowing experimental research into the pathogenetic mechanisms of the disease to begin. In the clinic, the identification of disease genes can lead to the development of accurate, efficient, and specific diagnostic tests. The proliferation of neurologic disease genes, however, exceeds the capability—and probably the necessity—for clinical laboratories to establish clinical diagnostic tests. Each gene and disease-causing mutation is unique, requiring a unique assay. The possibilities of nondetection of a relevant gene mutation (false-negative results), detection of DNA sequence variants of uncertain relevance to the patient (uncertain results), and gene mutations unrelated to the patient’s disease (false positives) are also unique to each gene, assay, and disease and require significant expertise to understand and explain to patients. We review the clinical situations in which gene tests are typically used and then review the genetic forms of ataxia and spastic paraplegia for which genetic testing is possible in early 2005. Printed materials are only current at the time they are written; for up-to-date information about any particular condition or test, readers are urged to consult online references such as GeneTests (www.genetests.org).

Clinical Use of Gene Tests DIAGNOSTIC TESTING There are five clinical situations in which genetic testing can be used: diagnostic testing, prenatal testing, predictive testing, carrier testing, and genetic risk factor assessment. Of these, the most straightforward and familiar scenario to the physician

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is that of diagnostic testing. In this scenario, a patient has consulted the physician because of symptoms and, during the course of the evaluation, the possibility of a genetic diagnosis arises. In the context of the ataxias and spastic paraplegias, the presence of a similarly affected family member or the appearance of a progressive degenerative condition might lead the physician to consider a genetic diagnosis. From the medical perspective, it is always of value to pursue a specific genetic diagnosis rather than a general descriptive one, for several reasons. For instance, even if the patient’s therapy does not change as a result of a diagnosis of “spinocerebellar ataxia type 3” (SCA3), rather than a general diagnosis such as “hereditary ataxia” or “ataxia,” the specific diagnosis ends forever the patient’s quest for an explanation for his or her symptoms, allows disease-specific prognostic information to be given, and permits accurate genetic counseling for the patient and other family members. Unfortunately, financial concerns may limit some patients’ ability to undergo a gene test, as some insurers decline to pay for certain gene tests, and while some gene tests are relatively inexpensive, the cost of others may be in the thousands of dollars. Physicians who order diagnostic gene tests have two burdens of communication. First, they must convey to the patient an accurate interpretation of the test results and their relationship to the patient’s symptoms. Second, knowing that the results of a gene test have direct implications to the health of others, including the children and potential children of the patient, as well as siblings, parents, and more distant relatives, the physician must provide or refer the patient for genetic counseling. Clinical diagnostic laboratories, online resources such as Online Mendelian Inheritance in Man (OMIM) (www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM) and GeneTests (www.genetests.org), and genetic counselors and other genetics professionals can all serve as resources to the physician who needs assistance in interpreting the relevance to the patient of a gene test result, or in identifying genetic counseling resources for the patient or family. The utility of gene tests for indications other than diagnostic evaluation is affected by the sometimes complex or uncertain relationship between the presence of the gene mutation and the development of the disease. For the trinucleotide repeat disorders, a relationship between the size of the gene mutation and the age at symptom onset is often noted, and symptoms often do not begin until well into adulthood. For many disorders, genetic heterogeneity, allelic heterogeneity, and variable expressivity of disease symptoms in the presence of the gene mutation all restrict the utility of gene tests for nondiagnostic purposes. An excellent example of all three of these issues is presented in the review by Jen et al.1 of episodic ataxia type 2 (EA-2). They identified 18 families and 9 sporadic cases of clinically defined EA-2. Eleven of 18 families showed linkage to the chromosome 19p locus of CACNA1A (implying that as many as seven families could have had a different genetic cause for their condition). Mutations were found in 9 of 11 families and in 4 of 9 sporadic cases. All 13 mutations were unique, and only 2 had previously been reported, demonstrating allelic heterogeneity of CACNA1A-linked EA-2. Finally, a wide range of clinical symptoms were seen in the 64 subjects of the study, including migraine headaches, seizures, vertigo, and progressive ataxia, in addition to episodic ataxia (present in all but two subjects).

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PRENATAL AND PREIMPLANTATION TESTING Prenatal and preimplantation genetic testing provide genetic information about an unborn being. Prenatal testing requires the acquisition of fetal tissue by amniocentesis or chorionic villus biopsy, whereas preimplantation testing involves in vitro fertilization of several oocytes, testing of a single cell from each of the resulting embryos, and the subsequent implantation of embryos documented to be free of the gene mutation of interest. Neither prenatal nor preimplantation testing can be performed unless the specific gene mutation in the family has been documented in an affected individual, and both require a firm understanding on the part of the requesting couple of their own reproductive risks and the predictive value of the test, as well as an understanding of the potential risks, benefits, and outcomes of the testing process. To date, there has been no disease-preventing or diseasemodifying treatment reported for any of the ataxias or spastic paraplegias that would be applicable in the prenatal setting, so the only treatment decision that might depend on the outcome of a prenatal test would be termination of the pregnancy. Ordinarily, counseling and discussion about prenatal and preimplantation tests is provided by a genetic counselor working with an obstetrician/gynecologist. It is theoretically possible for an individual at risk for a dominantly inherited disorder, such as one of the CAG repeat disorders, to undergo prenatal exclusion testing. To accomplish this, samples are obtained from the fetus, the at-risk individual and partner, as well as both of the at-risk individual’s parents. DNA markers genetically linked to the disease gene locus are tested to determine whether the fetus has inherited markers that came from the at-risk individual’s affected parent or from the unaffected parent. If the fetus has inherited genetic markers from the atrisk individual’s unaffected parent, then the possibility that the fetus has inherited the disease-causing gene has been excluded. Prenatal (or preimplantation) exclusion testing does not confront the at-risk individual with his or her own genetic status but allows the certainty of a pregnancy free of the gene mutation. In practice, it may be difficult for a clinician to find a clinical laboratory to undertake the analysis of gene-linked markers; a research laboratory, which may be able to perform such an analysis, may be restricted from providing it as a clinical service. Advance planning is required for anyone desiring prenatal exclusion testing. The uptake of prenatal testing and preimplantation testing for hereditary ataxias and spastic paraplegias, other than those with childhood onset, appears to be low. PREDICTIVE TESTING Predictive, or presymptomatic, testing refers to the use of a gene test by an asymptomatic adult who is known to be at risk for developing a specific genetic disorder (usually because a parent or sibling is affected). In the case of the ataxias and spastic paraplegias, there is currently no medical treatment to be offered on the basis of a positive predictive gene test result, so the only potential benefits to the patient are psychosocial ones. These potential benefits should be carefully weighed before testing against the potential psychosocial risks, including the potential negative impact on insurability, employability, self-perception, and relationships with friends and family. Based on studies of the ethical, legal, and social implications of predictive testing, clinical protocols have been established for Huntington’s disease (HD), which include the following steps: pretest genetic counseling, psychologic assessment, and possibly neurologic examination; freely given informed consent; time to reassess

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the decision to be tested; and predictive test results to be given in person in the context of supportive counseling.2,3 In the United States, a small percentage of atrisk individuals select predictive testing for HD. Only in very unusual circumstances would predictive testing of a child be warranted, and predictive testing of nonconsenting adults is likewise to be avoided. Surveys of members of large kindreds at risk for SCA1, SCA2, and SCA3 have shown a high interest (at least 75%) in predictive and prenatal testing for these conditions,4–6 although the experience is that a much lower proportion of at-risk individuals actually choose to undergo clinical testing.7 The distinction between a predictive test and a diagnostic test can be somewhat blurry, as there may be an urge on the part of either the patient or the physician to proceed with a gene test on the basis of symptoms that are vague, minimal, or not necessarily related to the disease (testing a patient at risk for SCA2 who presents with fatigue, depression, and headache, for instance, or testing a healthy patient at risk for SPG4 who has unexpected isolated ankle clonus). The physician should make it clear to the patient whether he or she views the test as a diagnostic one or a predictive one and should obtain the consent of the patient before ordering a test, with an advance discussion of the potential implications of the genetic diagnosis. Caution is particularly important for conditions such as SPG4, in which disease expression is extremely variable. Individuals with minimal symptoms may not view themselves as affected and may never develop functionally limiting symptoms. In this situation, the physician should balance carefully with the patient the potential psychosocial risks of a genetic diagnosis of SPG4 in the presence of minimal symptoms against the benefits of knowing the reproductive risks. CARRIER TESTING Carrier testing is relevant for the relatives of individuals with X-linked or autosomal recessive genetic conditions. Unaffected relatives in these families may carry two copies of a normal gene, or they may carry one copy of a normal gene and one copy of the mutation-carrying gene. Those who carry two normal genes have no risk of passing a disease gene to their children, whereas those who are carriers of a single copy of the abnormal gene can pass that gene on to their children (who would then also be carriers), and depending on the contribution from the child’s other parent, could be at risk of having affected children. It is possible for both patients and third parties (e.g., insurers and employers) to equate the diagnosis of the carrier state with the diagnosis of a disease, which is generally not the case (although for some X-linked conditions such as the SPG2/ proteolipid protein [PLP] spectrum, female carriers can have disease symptoms). Careful genetic counseling should be provided before a patient undergoes carrier testing.8 GENETIC RISK FACTOR ASSESSMENT Risk factor assessment will likely be the next growth area in the field of genetic testing. This refers to the ascertainment of genetic status for genes that might modify the risk that a person will develop a disease, condition, or benefit or side effect from a medication. Risk factors relevant to spastic paraplegia or ataxia are not known.

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Genetic Testing for Hereditary Ataxia A search of the encyclopedic OMIM (March 30, 2006) for conditions including the word “ataxia” yields a staggering 609 entries, which is itself a clue to the sensitivity of the cerebellum to insults of many varieties. Without including every single descriptively named syndrome in the list, we have attempted to categorize the more important syndromes in Table 18-1. In general, conditions that include ataxia as a prominent symptom fall into several categories: metabolic disorders, mitochondrial disorders, disorders that include structural anomalies of the cerebellum, disorders of premature aging, and a diverse group of chronic, often neurodegenerative, conditions that share ataxia/incoordination as the most prominent feature. We focus on molecular diagnostic testing for the degenerative ataxias, which are often clinically indistinguishable from each other, and for which genetic testing provides the only means to a specific diagnosis. Conditions for which gene tests are available are shown in Table 18-2. Aspects of the presentation that can guide the clinician through a maze of acquired conditions and more than 500 genetic entities to decide which tests to order include: the age at symptom onset, the patient’s gender and ethnic or geographic background, the presence or absence of organ involvement outside the nervous system, the presence of a “pure” cerebellar versus a “complicated” multisystem neurologic phenotype, the extent and location of brain atrophy or other magnetic resonance imaging findings,9,10 and the presence or absence and nature of the family history. The single most common genetic form of ataxia is Friedreich’s ataxia (FA), an autosomal recessive condition that is likely to appear de novo without previous affected family members. As the FA phenotype is now recognized to extend into adulthood, an FA gene test may be useful even in an adult without any family history of ataxia.11 Worldwide, SCA3 is the most common of the dominantly inherited ataxias, with SCA2 and SCA6 slightly less common, and all other forms accounting for less than 10% of cases each. However, the relative frequencies of adult SCAs vary dramatically in different geographic regions.12–14 The dominant ataxias most likely to present de novo in an adult without a family history are SCA2, SCA6, SCA7, and SCA8.11 Both SCA2 and SCA7 have been reported as devastating illnesses in young children before the onset of symptoms in the parent.15 A clinical approach to the use of gene tests in the ataxias has been discussed,16 and GeneTests (www.genetests.org) is an excellent online resource for clinicians. It lists laboratories performing genetic tests for many disorders, along with contact information for the laboratories, clinical summaries of the diseases, and general descriptions of genetic concepts and testing methods. Most of the conditions listed in Table 18-2 are repeat expansion disorders, which can be subdivided from a genetic perspective into two subgroups. The mutation in a type 1 repeat expansion disease is located within the protein-encoding portion of the gene. Expansion of the repeat sequence leads to the production of an enlarged protein. In the case of the polyglutamine diseases, which include many of the ataxias, the enlarged protein contains an elongated section of glutamine moieties; this may lead to altered function of the protein, enhanced breakdown of the molecule by glutaminases, or other pathogenic processes. In type 1 repeat expansion diseases, there appears to be a constraint on the normal number of allowable CAG repeats, as well as a constraint on the abnormal repeat lengths. Table 18-3 shows the normal and abnormal repeat ranges for the repeat expansion diseases. For most type 1

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TABLE 18–1

Hereditary ataxia syndromes listed in Online Mendelian Inheritance in Man

Cerebellar ataxias, spinocerebellar ataxias Spinocerebellar ataxias types 1–8, 10–23, 25–26 Episodic ataxias types 1–4 Ataxia with oculomotor apraxia ARSACS DRPLA SAX1 Cerebellar ataxias 1–3 Cerebelloparenchymal disease 1, 2 Cayman cerebellar ataxia Metabolic disorders Aceruloplasminemia Alexander disease Argininemia Arginosuccinic aciduria Behr disease Biotinidase deficiency, holocarboxylase synthetase deficiency Carbamoyl phosphate synthetase deficiency Carnitine acetyltransferase deficiency Ceroid lipofuscinoses Coenzyme Q10 deficiency Gaucher disease Glutaric aciduria GM-1, GM-2 gangliosidoses Hartnup disease Hydroxykynureninemia L-2 alpha hydroxyglutaric aciduria Mannosidosis, alpha and beta Maple syrup urine disease Menkes disease 3-alpha methylglutaconic aciduria Methylmalonic aciduria Mevalonic aciduria Mucolipidosis Mucopolysaccharidosis 3A Neuraminidase deficiency Niemann–Pick disease Ornithine transcarbamylase deficiency 5-Oxoprolinuria Pyruvate decarboxylase deficiency Pyruvate dehydrogenase deficiency Refsum disease Ribose-5-phosphate isomerase deficiency Sandhoff disease Sarcosinemia Sea-blue histiocyte disease Sepiapterin reductase deficiency Sialic acid disorders (sialuria, sialic acid deficiency, sialidosis)

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TABLE 18–1

Hereditary ataxia syndromes listed in Online Mendelian Inheritance in Man—cont’d

Succinic semialdehyde dehydrogenase deficiency Tay-Sachs disease Tyrosinemia Mitochondrial disorders Complex 1 deficiency Kearns–Sayre syndrome Leber optic atrophy Leigh syndrome MELAS Mitochondrial DNA breakage syndrome MNGIE NARP PEO Structural disorders Dandy–Walker malformation Joubert syndrome Megalencephaly syndromes Vanishing white matter disease Vermis aplasia Premature aging/ DNA repair disorder syndromes Bloom syndrome Cockayne syndrome DeSanctis–Cacchione syndrome Rothmund–Thompson syndrome Seckel syndrome Xeroderma pigmentosum Trichothiodystrophy

repeat expansion disorders, normal repeat numbers range no higher than the 30s or 40s, and abnormal repeat numbers more than 100 are rare. Specific polymerase chain reaction (PCR)–based assays can accurately detect repeat expansions up to about 80–100 repeats but can miss very large expansions.15 Assays to screen for large expansions have been developed17 but are not routinely used in clinical diagnostic laboratories. For several conditions, overlap between the normal and abnormal repeat length ranges has been reported (Table 18-3). In the type 2 repeat expansion diseases, the region containing the repeat expansion is in a noncoding section of the gene. There appear to be fewer constraints in this situation on both the type of repeat sequence (which can be a tetranucleotide or pentanucleotide sequence) and the ranges of both the normal and the abnormal repeat lengths (e.g., abnormal repeat lengths in the frataxin gene ranging from 120 to 1700 GAA repeats have been reported). TYPE 1 REPEAT EXPANSION DISEASES SCA types 1, 2, and 3 are all multisystem neurodegenerative disorders with typical onset in mid-adulthood, with ataxia as a prominent feature but also frequently but

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TABLE 18–2

Hereditary ataxias for which gene testing is possible

A. Autosomal dominant inheritance pattern Locus name

Chromosome

Protein

Mutation type

SCA1 SCA2 SCA3 SCA6 SCA7 SCA8 SCA10 SCA12 SCA14 SCA17 DRPLA EA1 EA2

6p 12q 14q 19p 3p 13q 22q 5q 19q 6q 12p 12p 19p

Ataxin-1 Ataxin-2 Ataxin-3 CACNA1 Ataxin-7 Ataxin-8

CAG expansion CAG expansion CAG expansion CAG expansion CAG expansion CTG expansion ATTCT expansion CAG expansion Point mutations CAG expansion CAG expansion Point mutations Point mutations

PP2R2B PKCγ TBP Atrophin-1 KCNA 1 CACNA1A

B. Autosomal recessive inheritance pattern Locus name

Chromosome

Protein

Mutation type

Friedreich’s ataxia (FA)

9q

Frataxin

Ataxia/vitamin E deficiency Cayman ataxia Abetalipoproteinemia Ataxia-telangiectasia (AT) Ataxia/oculomotor apraxia 1 Ataxia/oculomotor apraxia 2 AT-like disorder SCAN 1 ARSACS

8q 19p 4q 11q 9p 9q 11q 14q 13q

α-TTP ATCAY MTP ATM Aprataxin Senataxin MRE 11 TDP Sacsin

GAA expansion, point mutations Point mutations Point mutations Point mutations Point mutations Point mutations Point mutations Point mutations Point mutations Point mutations

Note: ARSACS, autosomal recessive spastic ataxia of Charlevoix–Saguenay; ATCAY, cayman ataxia protein; ATM, ataxia-telangiectasia mutated; ATTCT, adenine-thymine-thymine-cytosine-thymine; CACNA1, calcium channel A1; CAG, cytosine-adenine-guanine; CTG, cytosine-thymine-guanine; DRPLA, dentatorubropallidoluysian atrophy; EA, episodic ataxia; GAA, guanine-adenine-adenine; KCNA1, potassium channel A1; MRE 11, meiotic recombination-11; MTP, microsomal triglyceride transport protein; PKCγ, protein kinase C gamma subunit; PP2R2B, protein phosphatase subunit 2R2B; SCA, spinocerebellar ataxia; SCAN, spinocerebellar ataxia/axonal neuropathy; TBP, TATA-binding protein; TDP, topoisomerase I–dependent DNA repair enzyme; αTTP, alpha tocopherol transfer protein.

variably including spasticity (SCA1 and 3), parkinsonism (SCA2 and 3), amyotrophy, dystonia (SCA3), dementia (SCA2), slow saccades (SCA1 and 2), and neuropathy (SCA1). SCA3 is also known as Machado–Joseph disease, because of its description in these families of Portuguese/Azorean descent, and was the condition affecting the “Drew Family of Walworth,” described by Gowers et al.18 In a single individual,

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TABLE 18–3

Normal and abnormal repeat ranges for repeat expansion disorders

Gene/disease

Repeat sequence

Normal

Intermediate

Abnormal

SCA1 SCA2 SCA3 SCA6 SCA7 SCA 17 DRPLA FA SCA8 SCA10 SCA12

CAG CAG CAG CAG CAG CAG CAG GAA CTG ATTCT CAG

6–44 15–32 12–47 3–18 7–35 25–42 <36 6–40 15–50 10–22 7–31 (45)

36–38 32–33 48–51 19 28–35 42–44? 48–93 37–66 50–70? 280–4500 55–78

39–91 (32) 33–77 (500) (45) 51–86 (19) 20–33 36–300 44–66 66–1700 (71) 80–800?

Note: Numbers in parentheses are based on single case reports.

these conditions cannot reliably be clinically distinguished, so tests for all three are often ordered simultaneously. In certain ethnic groups or geographic regions, one or another of these conditions may be much more common, and testing can be directed appropriately. Collectively, these three forms of hereditary ataxia account for about 40% of dominantly inherited ataxias in the United States. Overlap of the normal and abnormal CAG repeat ranges has been reported and is particularly noticeable for SCA2, leading one group to make available a molecular ladder of known repeat lengths to facilitate accurate counting of CAG repeats in this critical range.19 A second laboratory has developed methods for discriminating between alleles in patients who appear to carry two SCA3 alleles of the same CAG repeat length.20 Several SCA3 homozygotes have been reported, with variable phenotypes.21,22 Predictive testing for SCA1 and SCA3 by CAG repeat analysis has been reported by a number of authors,7,23,24,25–29 as has prenatal testing.30,31 Preimplantation testing with successful birth of an unaffected child has been reported for SCA3.32 SCA type 6 typically presents with a “pure” cerebellar ataxia involving limbs, gait, dysarthric speech, and nystagmus, but generally without a complex neurologic phenotype until later in the disease, when impairment of position and vibration sense, restricted upward gaze, and upper motor neuron findings may be present. SCA6 appears to be particularly common in Japan and Germany, accounting for 13 and 21% of dominant ataxias, respectively. Patients homozygous for expanded alleles have been reported several times in Japan.33 SCA type 7 can be distinguished from other SCAs by the presence of retinal degeneration.34 Along with SCA2, this form of ataxia has also been associated with extreme examples of in utero or neonatal symptom onset associated with extreme expansions of the CAG repeat sequence during paternal meiosis.15 Prenatal testing has been reported.35 SCA type 17 was first described in Japan and appears to be rare in the United States. In this condition, ataxia is often accompanied by cognitive decline, bradykinesia, dystonia, and sometimes epilepsy.36 The CAG repeat sequence in the TATA-

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binding protein (TBP) gene normally contains up to 44 repeats but, in the expanded state, carries 48 or more repeats.37,38 Onset at age 3 years with rapid progression and early death was reported in a child with 66 CAG repeats,39 as was a homozygote presenting with chorea and dementia.40 Dentatorubropallidoluysian atrophy (DRPLA) is extremely uncommon in the United States but notably more common in Japan. In the United States, mutations in the atrophin-1 gene have been associated with the Haw River syndrome in a large North Carolina family of African descent.41 Phenotypically, these conditions tend to include myoclonus and seizures, chorea, and cognitive decline in addition to ataxia. Homozygosity for intermediate-length expansions was reported in consanguineous siblings presenting with spastic paraplegia.42 TYPE 2 REPEAT EXPANSION DISEASES FA is the single most common form of hereditary ataxia. It is a recessively inherited condition, with a carrier frequency estimated at about 1/100. Before the discovery of the frataxin gene, the diagnosis of FA was clinically defined43; genetic analysis has now proven that FA has a broader phenotypic range than was previously recognized, with cases of adult onset (late-onset FA [LOFA]), or cases with incomplete phenotypes (FA with retained reflexes [FARR]; spastic paraplegia) showing frataxin gene GAA expansions.44,45 The size of the smaller GAA repeat expansion has a relationship to the clinical presentation, with larger repeat expansions associated with multisystem involvement (cardiomyopathy, diabetes) or more severe or earlier onset of neurologic symptoms.46,47 Prenatal testing for FA by GAA repeat expansion analysis has been reported.48 Up to 95% of mutation-bearing frataxin genes have GAA repeat expansions, but clinical experience suggests that about 4–5% of abnormal alleles carry some other type of mutation, such as a point mutation. This complicates molecular diagnostic testing somewhat, as detection of private point mutations is not possible with the assay used to detect repeat expansions, and may require expensive and laborious sequencing of the gene. Sound clinical judgment must accompany the interpretation of gene test results in a patient whose phenotype suggests FA but in whom only one GAA expansion is detected.49 Caution must be used also when repeat lengths are in the intermediate range; a report highlights the diagnostic difficulties.50 FA has not been reported in the Southeast Asian or African populations. CTG repeat expansions in the SCA8 gene have been associated with ataxia in certain families.51,52 The relationship between CTG expansions and disease symptoms remains a little uncertain, however, because individuals with large CTG repeat expansions may not have disease symptoms (reduced penetrance), and in some populations, CTG expansions are seen in up to 0.6–2.9% of healthy individuals and in 1% of patients with psychiatric diagnoses not accompanied by ataxia.53,54 It remains unclear whether there is simply incomplete penetrance of potentially disease-causing mutations, whether there is a bimodal “normal” repeat range,55 and which phenotypes should be accepted as SCA8 associated.56 Diagnostic results of an SCA8 gene test, therefore, must be interpreted with caution, especially if they are being used for prenatal or predictive testing.53 SCA10 was described in a Mexican family and, in this family, includes seizures as a prominent part of the phenotype.57 It appears to be rare in other ethnic and geographic settings.58,59

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SCA12 was described in a family whose members typically presented first with action tremor of the arms, later developing ataxia, bradykinesia, head tremor, and abnormal eye movements. The CAG repeat sequence is located in the 5′ untranslated region of the protein phosphatase subunit gene, PPP2R2B.60,61 Additional families of European American and Indian descent have been reported. OTHER RECESSIVELY INHERITED ATAXIAS Ataxia with vitamin E deficiency yields a variable phenotype that resembles that of FA, with the childhood onset of ataxia and dorsal column dysfunction.62,63 The diagnosis of this condition is usually made by measurement of vitamin E levels rather than by molecular genetic diagnosis. Abetalipoproteinemia can also present with a phenotype similar to that of FA but also produces acanthocytes on peripheral blood smear, as well as additional clinical features such as malabsorption in early childhood. Cayman ataxia is an early-onset autosomal recessive condition so far known only on the Grand Cayman Islands, usually presenting with psychomotor retardation and ataxia.64 Ataxia-telangiectasia (AT) has a complex multiorgan phenotype, including immune deficiency, high incidence of hematologic malignancies, gonadal failure, and truncal instability, abnormal eye movements, ataxia, and hypotonia.65 Problems usually become obvious within the first decade, but incomplete phenotypes are possible. Because more than 400 mutations within the large ATM gene have been reported, accurate molecular genetic diagnosis may require gene sequencing and is not routinely available.66 The addition of molecular screening methods, such as reverse transcriptase PCR (RT-PCR), before sequencing may improve the efficiency of the laboratory analysis.67 Other laboratory studies, such as analysis of α-fetoprotein level, chromosome analysis, and ultraviolet sensitivity of cultured fibroblasts, can help in the diagnosis when gene testing is not possible or results are unrevealing. Prenatal testing by mutation detection has been reported,68 and preimplantation testing was performed in one family with a large deletion in the ATM gene.69 An AT-like condition caused by mutations in the MRE11 gene has been reported in several Saudi Arabian families.70 Genetic analysis of the aprataxin gene responsible for ataxia with oculomotor apraxia (AOA) type 1 is available. This condition usually presents within the first two decades with ataxia, sensory neuropathy, and oculomotor apraxia; it is common in Japan but uncommon in Europe.71,72 AOA2 and SCA with axonal neuropathy are other clinically similar conditions for which routine genetic diagnosis is not available.73,74 Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is caused by a mutation in the sacsin gene; this condition is common in an isolated region of Quebec.75,76 OTHER DOMINANTLY INHERITED ATAXIAS SCA type 14 includes head tremor and myoclonus in addition to ataxia, with onset usually in young adulthood. Unique among the known adult-onset degenerative ataxias, this condition is associated with point mutations, rather than repeat expansions, in the protein kinase C γ gene.77–79 Diagnostic testing is not routinely available in the United States for this rare disease.

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EA types 1 and 2 are caused by mutations in ion channel genes, KCNA1 and CACNA1A, respectively.1,80 As the responsible mutations are point mutations, which may be unique to the individual, molecular diagnosis may be expensive (gene sequencing) or may only suggest, rather than identify (various mutation screening methods), mutations. Notably, whereas point mutations in the CACNA1A gene cause EA-2 or the distinct clinical entity, familial hemiplegic migraine, CAG repeat expansions in the same gene are the cause of SCA6. Some patients beginning with an EA-2 phenotype later develop progressive ataxia reminiscent of SCA6. Rare families with EA not linked to mutations in the two known genes have also been identified.

Fragile X–Associated Tremor Ataxia Syndrome Fragile X–associated tremor ataxia syndrome (FXTAS) is a newly described condition that is proving to be an important cause of late-onset sporadic progressive gait ataxia with associated tremor, parkinsonism, or autonomic features.81–83 Researchers studying the fragile X syndrome in children with mental retardation became aware of this phenotype in nonretarded male family members older than 50 years and found that it was associated with the presence of “premutations” in the fragile X gene.81 The normal fragile X gene contains 7–55 CGG repeats in the noncoding portion of the gene. Full gene mutations of more than 200 CGG repeats are inherited from carriers of premutations containing 55–200 repeats. Full repeat expansions in this gene appear to interfere with the production of the FMR-1 protein, so males with fragile X syndrome produce insufficient quantities of the protein. Female carriers are protected from symptoms by the presence of a second allele on their other X chromosome, so that neurologic symptoms of either FXTAS or fragile X–related mental retardation are more likely in men. Fragile X premutations are not associated with mental retardation and were not thought to be related to any disease phenotype until the discovery of FXTAS.

Hereditary Spastic Paraplegia The hereditary spastic paraplegias (HSPs) are an etiologically and phenotypically diverse group of diseases. Although more than 20 causative genetic loci have been mapped, identification of the actual genes has lagged behind, and clinical testing is restricted to a small number of clinical and research laboratories. For the patients and families who obtain a specific diagnosis as a result of genetic testing, however, its importance should not be underestimated. A search of the OMIM using the term “spastic paraplegia” yields 133 entries (www.ncbi.nlm.gov.entrez/query; March 30, 2006). At least 27 of these are entries for genes rather than diseases, leaving about 100 disease entries. Table 18-4 categorizes the remaining entries, after consolidating duplicates. Many of these are unique syndromes described in one or a few families; others, like lissencephaly and cerebrotendinous xanthomatosis, would probably not be categorized by a clinician as HSPs, although limb spasticity may be part of the neurologic syndrome. The

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TABLE 18–4

Hereditary spastic paraplegia syndromes listed in Online Mendelian Inheritance in Man

“Pure spastic paraplegias” SPG3/atlastin SPG4/spastin SPG5A SPG6/NIPA1 SPG8 SPG10, 11, 12, 13, 19, 24 “Complicated spastic paraplegias” SPG2/Pelizaeus–Merzbacher disease SPG5A SPG7/paraplegin SPG17/Silver syndrome SPG20/Troyer syndrome/spartin SPG15, 16, 25, 26, 27 Infantile ascending hereditary spastic paralysis/alsin Metabolic disorders Alpha galactosidase deficiency (Fabry disease) Argininemia 3-Methylglutaconic aciduria types 3 and 4 Homocarnosinosis Gaucher disease Mannosidosis Autosomal mental retardation/spastic paraplegia syndromes Pure With ataxia With deafness, nephropathy With epilepsy With glaucoma With limb defects With palmoplantar hyperkeratosis With retinitis pigmentosa SPG14/with neuropathy X-linked mental retardation/spastic paraplegia syndromes Five syndromes Brain malformation syndromes SPG1/aqueductal stenosis/Xq28 syndromes SPG11/with thin corpus callosum Agenesis of the corpus callosum Dandy–Walker malformation Fryns syndrome Miller–Dieker lissencephaly Paine syndrome Ataxia syndromes Spinocerebellar ataxia type 1 Cerebellar ataxia type 2 Olivopontocerebellar atrophy type 4 Spastic ataxia Table continued

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TABLE 18–4

Hereditary spastic paraplegia syndromes listed in Online Mendelian Inheritance in Man—cont’d

Hereditary neuropathy syndromes Charcot–Marie–Tooth (CMT) disease type 1B CMT X Hereditary motor and sensory neuropathy type 5 Sensory neuronopathy With dementing conditions With early-onset Alzheimer’s disease (Presenilin 1) SPG21/Mast syndrome Amyotrophic lateral sclerosis (ALS) syndromes ALS2/alsin ALS5 With other types of movement disorder With dystonia Paroxysmal nonkinesogenic dyskinesia Episodic choreoathetosis Amyotrophic dystonic paraplegia With extrapyramidal symptoms With other neurologic conditions With myoclonic epilepsy Diffuse cerebral sclerosis Fahr disease Spinal muscular atrophy type 5 Cerebrotendinous xanthomatosis With eye anomalies Laurence–Moon syndrome Bardet–Biedl syndrome Waardenburg syndrome With optic atrophy With optic atrophy and dementia With optic atrophy, microcephaly, and XY sex reversal SPG9/with cataracts and motor neuronopathy With bone anomalies Oculodental-digital dysplasia Fitzsimmons–Guilbert syndrome With metaphyseal modeling Type 3 syndactyly With blood anomalies Evans syndrome with spastic paraplegia X-linked immune disorder With May–Hegglin anomaly Cryohydrocytosis with spastic paraplegia With skin anomalies With poikiloderma Lamellar ichthyosis With palmoplantar keratoderma SPG23/with skin pigment changes With endocrine anomalies Adrenoleukodystrophy Kallmann syndrome with spastic paraplegia Congenital adrenal hyperplasia With precocious puberty

18 • Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia

inclusion in the table of conditions classified as hereditary neuropathies, motor neuron diseases, and ataxias illustrates the potential clinical overlap between these seemingly distinct neurologic disorders. Finally, some clinically important conditions that can present with spastic paraplegia are notably absent, including dopamineresponsive dystonia, autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS), SCA type 3 (Machado–Joseph disease), and several leukodystrophies that can occasionally present with complicated adult-onset spastic paraplegia. For the diagnosing clinician, the spastic paraplegias can be divided into four subcategories: nongenetic forms, syndromic forms (those that involve organ systems in addition to the nervous system), complicated forms (those that have complex neurologic phenotypes but do not involve other organ systems), and pure forms, in which spastic paraplegia is the dominant, though not always the sole, feature. Loci containing genes responsible for pure and complicated spastic paraplegia are often called “SPG” loci, numbered according to the order in which they were identified. We should point out that the presence of a similarly affected relative does not always ensure a genetic diagnosis. A patient diagnosed with tropical spastic paraparesis due to HTLV-1 infection, for instance, may live in or come from an endemic area and thus have many affected relatives. Likewise, chronic lathyrism is endemic in areas of the world where chickpeas are a dietary staple, and even multiple sclerosis, usually considered to be an acquired disease, may cluster in families due to genetic predisposing factors. We will not discuss the syndromic forms of spastic paraplegia further, as their diagnosis hinges more on the recognition of the pattern of abnormality than on genetic testing. Table 18-5 summarizes the SPG loci containing identified genes for which clinical or research testing are available. Other important identified genes include alsin (ALS2), presenilin 1 (Alzheimer’s disease with spastic paraplegia), and ABCD1 (adrenoleukodystrophy). Notably missing from the list of genetic forms of spastic paraplegia are any conditions involving a trinucleotide repeat expansion

Clinically testable spastic paraplegia genes

TABLE 18–5 Locus

Gene

Condition

SPG1

L1CAM

SPG2 SPG3A SPG4 SPG6 SPG7 SPG10 SPG13 SPG17 SPG20 SPG21

PLP2 Atlastin Spastin NIPA1 Paraplegin KIF5A HSPD1 Seipin Spartin Maspardin

XL SP with mental retardation, aqueductal stenosis/ hydrocephalus XL SP, Pelizaeus–Merzbacher disease AD pure SP AD pure SP AD SP AR SP AD pure SP AD pure SP Silver syndrome Troyer syndrome Mast syndrome

Note: AD, autosomal dominant; L1CAM, L1 cell-adhesion molecule; PLP, proteolipid protein; SP, spastic paraplegia; XL, X linked.

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(except for SCA type 3, a multisystem polyglutamine disorder that occasionally has gait spasticity as the predominant feature). For most of the spastic paraplegia genes, mutations are unique to each family or a small number of families. The low frequency of the spastic paraplegias in general (1–2/100,000 in Ireland84), along with the variety of mutations in each gene, conspires to make clinical diagnostic testing somewhat difficult to access.

Summary of Clinically Testable Spastic Paraplegias The L1CAM gene (SPG1) is an X-linked gene responsible for a spectrum of acronymed syndromes including hydrocephalus due to stenosis of the aqueduct of Sylvius (HSAS), mental retardation, aphasia, shuffling gait, adducted thumbs (MASA), and corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus (CRASH). Carrier females have been reported to have mild symptoms. The term “L1 spectrum” is now being used to encompass the range of neurologic and radiologic findings associated with mutations in this gene, which was identified in 1994.85,86 Clinical molecular genetic testing is available for diagnostic purposes, carrier testing, and prenatal testing.87–89 A variety of mutations in the gene have been identified, including missense and truncating mutations. One report indicates that mutations are detected in 75% of clinically diagnosed patients.90 The PLP1 gene (SPG2) is responsible for a syndrome that ranges from pure spastic paraplegia to Pelizaeus–Merzbacher disease, a fatal leukodystrophy. The clinical, genetic, and pathophysiologic features of SPG2/PMD have been reviewed.91–93 The assignment of the PLP1 gene to the X chromosome in 1985 was one of the early successes in human gene mapping.96 A wide variety of mutations in the gene have been identified, including point mutations, gene deletions and duplications, and complex chromosomal rearrangements. Several authors have emphasized a lack of correlation between the gene mutation and disease phenotype, but one author has suggested that point mutations are more likely to result in severe phenotypes, while mutations that would lead to loss or inactivation of the protein are more likely to lead to mild phenotypes.95 Female carriers of this X-linked gene can have mild symptoms. Prenatal testing for PMD has been reported,96 and diagnostic and carrier testing is clinically available. No single laboratory method will detect all of the possible types of mutation. Both X-linked (SPG16) and autosomal recessive “PMD-like” conditions have been reported.97,98 Genetic analysis of the atlastin gene (SPG3A), located on chromosome 14q11-21, is available in clinical and research laboratories. It has been estimated that SPG3A accounts for 10–39% of non-SPG4 autosomal dominant spastic paraplegia, or about 9% of all cases.99 At least 10 distinct mutations in the gene have been identified, but a number of unrelated kindreds of European origin have shared a common mutation, R239C. Reports of atlastin gene analysis have come from the United States, Great Britain, France, Germany, and Italy.100–106 One African American family has been reported.103 Incomplete penetrance has been reported for this autosomal dominant disorder.107 Most patients have had early childhood-onset of this relatively indolent condition, which may include scoliosis and distal muscle wasting, but appears otherwise to be a “pure” or “uncomplicated” form of autosomal dominant spastic paraplegia. Prenatal testing by direct gene analysis has not been reported

18 • Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia

in the literature but should be possible in a family with a previously defined mutation. Prenatal diagnosis using markers linked to the gene locus was reported in a research family.108 Mutations in the spastin gene (SPG4), located on chromosome 2p22, are recognized as the most common cause of autosomal dominant pure spastic paraplegia, responsible for about 15–50% of families, depending on location. Spastin mutations have been reported in patients of diverse ethnic origins, including Tunisian, Chinese, Japanese, and European (Germany, Italy, England).109–116 A variety of mutations have been reported, including frameshift and missense mutations, small insertions and deletions, splice-site mutations, a small intragenic duplication, and a deletion in the 5′ untranslated region of the gene. A founder effect was seen in nine “unrelated” families from southern Scotland who all carried the same novel point mutation.114 Intragenic polymorphisms have been reported to modify the disease phenotype in research families, but this finding has not been confirmed and is not used diagnostically.117 One report suggested a correlation between specific mutations and the clinical phenotype in two families,118 but most researchers have found the phenotype to vary substantially even within families. Genetic testing is available, and prenatal testing has been reported.119 With the wide range and private nature of the mutations so far reported, it is clear that no single laboratory technique will detect all mutations. The wide phenotypic range even within families limits the utility of predictive testing for this adult-onset condition. The NIPA1 gene, located in the SPG6 autosomal dominant spastic paraplegia locus on chromosome 15q11.1, was identified in 2003 and can be tested clinically.120 One report defined two novel mutations in unrelated Chinese families, both in codon 316, suggesting that this may be a common site for mutations in this gene.121 Mutations in the paraplegin gene at the SPG7 locus on chromosome 16q24.3 are responsible for autosomal recessive spastic paraplegia. The gene was identified in 1998 and molecular diagnostic testing can be performed.122 At least nine different mutations have been identified in this gene, which in one report was responsible for spastic paraplegia in 3 of 35 patients with either sporadic or apparently recessive inheritance.123 Mutations in the kinesin heavy chain gene KIF5A, located at the SPG10 locus on chromosome 12q13, were identified in a single U.S. family with pure spastic paraplegia.124 One additional multigeneration Italian family with this disease has been reported.125 Genetic testing is only available in a research setting. Mutations in the mitochondrial chaperonin Hsp60 at the SPG13 locus on chromosome 2q24-q34 were found in a single French family with autosomal dominant pure spastic paraplegia.126,127 No additional families with this condition have been identified, and clinical testing is not available. Silver syndrome (SPG17) is a well-described clinical entity that combines spastic paraplegia and distal muscle wasting in the hands.128 Heterozygous mutations in the Berardinelli–Seip congenital lipodystrophy gene (BSCL2, seipin), which is located within the SPG17 locus (11q12-q14), have been identified in several families with neurologic symptoms resembling those of Silver syndrome and distal hereditary motor neuropathy V (dHMN type V), and clinical testing for SPG17 has become available.128–130 The phenotype associated with BSCL2 mutations is somewhat variable, including patients with spastic paraplegia (Silver syndrome phenotype) to patients with a lower motor neuron–only phenotype (dHMN-V phenotype), with some showing features of both phenotypes.128–130

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Troyer syndrome (SPG20) was first described almost 4 decades ago in an Amish kindred.131,132 Thirty-five years after its first description, the causative gene mutation, a 1110delA single-base deletion in a gene now named spartin, was identified.133 This condition exists but appears to be rare outside the Amish population; whereas molecular diagnosis by mutation detection is possible within the Amish population, mutation analysis has not yet been reported in non-Amish patients. Another condition described decades ago in an Old Order Amish family, Mast syndrome (SPG 21) includes spasticity of adult onset and dementia.134 The responsible gene is named maspardin,125 and the causative mutation is a single base-pair insertion. Other families affected with this condition have not been reported. Table 18-6 summarizes the SPG loci in which disease-causing genes have not yet been identified. None of these genes or conditions are amenable to clinical genetic testing. However, patients with unknown forms of spastic paraplegia, particularly if they come from families in which there are multiple living affected individuals with the condition, may be of great interest to research laboratories. Of particular note is a gene in the SPG11 locus on chromosome 15q13-q15, which may be responsible for up to 50% of autosomal recessive pure spastic paraplegia.126 Extreme thinning of the corpus callosum is the distinguishing radiologic and pathologic feature of this disease. Affected individuals have been reported in Great Britain, Europe, Brazil, Japan, and China.126–141 Genetic testing is not clinically available, but a clinical diagnosis can be supported by brain MRI.

Other Conditions As noted in Table 18-4, a number of conditions that are not labeled “SPGs” may also have spastic paraplegia as a prominent feature. Infantile ascending hereditary

TABLE 18–6

Genetic loci containing as yet unidentified spastic paraplegia genes

Locus name

Chromosome

Condition

Reference

SPG5 SPG8 SPG9 SPG11 SPG12 SPG14 SPG15 SPG19 SPG22 SPG23 SPG24 SPG26

8p 8q23-q24 10q22.1-2q24.2 15q13-q15 19q13 3q27-q28 14q 9q33-q34 Xq21 1q24-q32 13q14 12p11.1-q14

AR pure SP AD SP SP AR SP with thin corpus callosum AD pure SP SP with MR, motor neuropathy AR SP AD SP Allan–Herndon–Dudley syndrome SP with abnormal skin pigment AR pure SP AR complicated SP

143, 144 145 146, 147 122 148, 149 150 151 152 153, 154 155 156 157

Note: AD, autosomal dominant; AR, autosomal recessive; MR, mental retardation; SP, spastic paraplegia.

18 • Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia

spastic paralysis (IAHSP) is an early childhood onset, very slowly progressive upper motor neuron disorder with corticospinal and corticobulbar effects.142 In one report, alsin (ALS2) mutations were found in 4 of 10 unrelated North African and European families with the phenotype of IAHSP; linkage to alsin was excluded in at least one family.143 An alsin mutation was also identified in a Pakistani kindred with spastic paraplegia.144 Alsin mutations have also been reported in association with two other phenotypes: juvenile-onset amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis.145 Mutations in the polyglutamine binding protein 1 were reported in more than 15% of families with both syndromic and nonsyndromic forms of X-linked mental retardation.146 Phenotypes in the affected individuals in these families included mental retardation, microcephaly, short stature, spastic paraplegia, and midline defects. If others confirm a similar high frequency in other populations, this may prove to be an important gene in clinical practice. Clinical testing of this gene is not available in the United States. Several patients and families with mutations in the presenilin 1 gene have been reported to develop spastic paraparesis along with or preceding dominantly inherited early-onset Alzheimer’s disease.147–150 The PS-1–associated phenotype is still being defined, as individual case reports have included a wide range of neurologic and radiologic features in addition to a rapidly progressive dementia and spastic paraplegia, including dystonia, dysarthria, and diffuse white matter abnormalities. The phenotype of dopa-responsive dystonia due to mutations in either the GTP cyclohydrolase gene or the tyrosine hydroxylase gene can include spastic paraplegia or exercise-induced spasticity.151,152 Both genes have been identified and can be clinically assayed; prenatal molecular diagnosis of tyrosine hydroxylase has been reported.153 We will mention briefly the oculodentodigital syndrome (ODD), having missed an opportunity a number of years ago to report what has since been reported by others: that this condition can result in adult-onset spastic paraplegia and MRI changes.154 The gene uniformly responsible for ODD is the connexin 43 gene, also called GJA1. Multiple missense mutations and one duplication were identified in the largest series of 17 families.155 There are insights to be gained from further study of the role of connexin 43 in the nervous system. Finally, of all the conditions that can cause spastic paraplegia, probably the most common and well-known one is adrenoleukodystrophy/adrenomyeloneuropathy. This X-linked condition is caused by mutations in the ABCD1 gene, which results in a phenotype ranging from a fatal childhood leukodystrophy to adult-onset spastic paraparesis; female hemizygotes, in particular, may present with a mild myelopathy. A case report emphasizes the possibility of multigenerational pure spastic paraplegia in an ALD/AMN family.156 The diagnosis of ALD is easily made in affected individuals by measurement of very long chain fatty acid levels in the plasma; mutation detection enhances the accuracy of the diagnosis.157

Conclusions The advent of genetic testing has facilitated accurate diagnoses for patients and families with genetic forms of ataxia and spastic paraplegia and has

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84. McMonagle P, Webb S, Hutchinson M. The prevalence of “pure” autosomal dominant hereditary spastic paraparesis in the island of Ireland. J Neurol Neurosurg Psychiatry 72:43–46, 2002. 85. Jouet M et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 1994;7:402–407. 86. Schrander-Stumpel C et al. Spectrum of X-linked hydrocephalus, MASA syndrome, and complicated spastic paraplegia (SPG1). Clinical review with 6 additional families. Am J Med Genet 1995;57:107–116. 87. Weller S, Gartner J. Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): mutations in the L1CAM gene. Hum Mutat 2001;18:1–12. 88. Silan F, Ozdemir I, Lissens W. A novel L1CAM mutation with L1 spectrum disorders. Prenat Diagn 2005;25:57–59. 89. Panayi M et al. Prenatal diagnosis in a family with X-linked hydrocephalus. Prenat Diagn 2005;25:930–933. 90. Schrander-Stumpel CT, Vos YJ. From gene to disease: X-linked hydrocephalus and L1CAM. Ned Tijdschr Geneeskd 2004;17:1441–1443. 91. Hudson LD. Pelizaeus–Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 2003;18:616–624. 92. Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus–Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005;6:1–16. 93. Koeppen AH, Robitaille Y. Pelizaeus–Merzbacher disease. J Neuropathol Exp Neurol 2002;61:747–759. 94. Willard HF, Riordan JR. Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders. Science 1985;230:940–942. 95. Cailloux F et al. Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet 2000;8:837–845. 96. Garbern J, Hobson G. Prenatal diagnosis of Pelizaeus–Merzbacher disease. Prenat Diag 2002;22:1033–1035. 97. Starling A et al. Further evidence for a fourth gene causing X-linked pure spastic paraplegia. Am J Med Genet 2002;111:152–156. 98. Uhlenberg B et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus–Merzbacher-like disease. Am J Hum Genet 2004;75:251–260. 99. Fink JK. Hereditary spastic paraplegia overview. GeneReviews. Available at: www.genetests.org. Accessed 1/21/05. 100. Abel A et al. Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. Neurogenetics 2004;5:239–243. 101. Dalpozzo F et al. Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation. Neurology 2003;61:580–581. 102. Durr A et al. Atlastin 1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. Arch Neurol 2004;61:1867–1872. 103. Hedera P et al. Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia. Arch Neurol 2004;61:1600–1603. 104. Sauter SM et al. Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat 2004;23:98. 105. Tessa A et al. SPG3A: an additional family carrying a new atlastin mutation. Neurology 2002;59:2002–2005. 106. Wilkinson PA et al. SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia. J Neurol Sci 2003;216:43–45. 107. D’Amico A et al. Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. Neurology 2004;62:2138–2139. 108. Hedera P et al. Prenatal diagnosis of hereditary spastic paraplegia. Neurology 2001;55:1592–1592. 109. Burger J et al. Hereditary spastic paraplegia caused by mutations in the SPG4 gene. Eur J Hum Genet 2000;8:771–776. 110. Falco M et al. Two novel mutations in the spastin gene (SPG4) found by DHLPC mutation analysis. Neuromuscul Disord 2004;14:750–753. 111. Hentati A et al. Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. Neurology 2000;55:1388–1390. 112. Iwanaga H et al. Large deletion involving the 5′-UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. Am J Med Genet A 2005;133A:13–17.

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113. Meijer IA et al. Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Arch Neurol 2002;59:281–286. 114. Orlacchio A et al. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol 2004;61:849–855. 115. Proukakis C et al. Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (spastin) gene. Hum Mutat 2003;21:170. 116. Tang B et al. Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. Arch Neurol 2004;61:49–55. 117. Svenson IK et al. Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 2004;5:157–164. 118. Bonsch D et al. Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. J Neurol Neurosurg Psychiatry 2003;74:1109–1112. 119. Nielsen JE et al. Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. Prenat Diagn 2004;24:363–366. 120. Rainier S et al. NIPA 1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG 6). Am J Hum Genet 2003;73:967–971. 121. Chen S et al. Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. Hum Mutat 2005;25:135–141. 122. Casari G et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloproteases. Cell 1998;93:973–983. 123. Wilkinson PA et al. A clinical, genetic, and biochemical study of SPG7 mutations in hereditary spastic paraplegia. Brain 2004;127:973–980. 124. Reid E et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 2002;71:1189–1194. 125. Fichera M et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004;63:1108–1110. 126. Fontaine B et al. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum Genet 2000;66:702–707. 127. Hansen JJ et al. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 2002;70:1328–1332. 128. Warner TT et al. A clinical, genetic, and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia. J Neurol 2004;251:1068–1074. 129. Windpassinger C et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004;36:271–276. 130. van de Warrenburg BP et al. BSCL2 mutations in two Dutch families with overlapping Silver syndrome–distal hereditary motor neuropathy. Neuromuscul Desord 2006;16:122–125. 131. Cross HE, McKusick VA. The Troyer syndrome: a recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 1967;16:473–485. 132. Proukakis C et al. Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol 2004;251:1105–1110. 133. Patel H et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 2002;31:347–348. 134. Cross HE, McKusick VA. The mast syndrome. A recessively inherited form of presenile dementia with motor disturbances. Arch Neurol 1967;16:1–13. 135. Simpson MA et al. Maspardin is mutated in Mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 2003;111:152–156. 136. Casali C et al. Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 2004;62:262–268. 137. Shibasaki Y et al. Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13-q15. Ann Neurol 2000;48:108–112. 138. Sperfeld AD et al. Complicated hereditary spastic paraplegia with thin corpus callosum: variation of phenotypic expression over time. J Neurol 2004;251:1285–1287. 139. Tang BS et al. Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of five Chinese cases. Chin Med J 2004;117:1002–1005. 140. Teive HA et al. Hereditary spastic paraplegia associated with thin corpus callosum. Arq Neuropsiquiatr 2001;59:790–792. 141. Winner B et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (APG 11). Arch Neurol 2004;61:117–121.

18 • Genetic Testing for Hereditary Ataxia and Hereditary Spastic Paraplegia

142. Devon RS et al. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet 2003;64:210–215. 143. Lesca G et al. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Neurology 2003;60:674–682. 144. Gros-Louis F et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol 2003;53:144–145. 145. Yang Y et al. The gene encoding alsin, a protein with three guanine–nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet 2001;29:160–165. 146. Kalscheuer VM et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet 2003;35:313–315. 147. Kwok JBJ et al. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer’s disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 1997;8:1537–1542. 148. Moretti P et al. Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology 2004;62:1865–1868. 149. O’Riordan S et al. Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI whitematter abnormalities. Neurology 2002;59:1108–1110. 150. Rogaeva E et al. PS1 Alzheimer’s disease family with spastic paraplegia: the search for a gene modifier. Neurology 2003;61:1005–1007. 151. Furukawa Y et al. Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations. Neurology 2001;56:260–263. 152. Tassin J et al. Levodopa-responsive dystonia: GTP cyclohydrolase I or parkin mutations? Brain 2000;123:1112–1121. 153. Moller LB et al. Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn 2005;25:671–675. 154. Nguyen K et al. Progressive spastic paraplegia as a presentation of oculodentodigital syndrome. Rev Neurol 2004;160:83–85. 155. Paznekas WA et al. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 2003;72:408–418. 156. Shaw-Smith CJ, Lewis SJ, Reid E. X-linked adrenoleukodystrophy presenting as autosomal dominant pure hereditary spastic paraparesis. J Neurol Neurosurg Psychiatry 2004;75:686–688. 157. Lautermacher MBR et al. Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously reported. Hum Mutat 2000;15:3438–3453.

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