Other autosomal recessive and childhood ataxias

Handbook of Clinical Neurology, Vol. 103 (3rd series) Ataxic Disorders S.H. Subramony and A. Du¨rr, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 21

Other autosomal recessive and childhood ataxias GIUSEPPE DE MICHELE* AND ALESSANDRO FILLA Department of Neurological Sciences, Federico II University, Naples, Italy

Autosomal recessive (AR) and childhood ataxias are here considered together, based on the argument that in most cases autosomal recessive inheritance and early onset coexist. The statement that onset of autosomal recessive ataxias occurs before age 20 is generally true, but many exceptions should be acknowledged. Friedreich ataxia is the most common autosomal recessive form and the prominent cause of ataxia in childhood and adolescence. Since the molecular test became available, it has been demonstrated that the right tail of the onset age distribution curve may extend to middle adulthood. The same concept applies to ataxia with oculomotor apraxia types 1 and 2, where adulthood onset has been seen. Furthermore, the onset of another autosomal recessive ataxia, cerebellar ataxia with hypogonadism, is more frequent after than before 20 years of age. On the other side, early-onset ataxia is not synonymous with autosomal recessive inheritance. The majority of the X-linked forms, as well as ataxias due to mtDNA mutations, begin in childhood or adolescence. Autosomal dominant adult-onset ataxias may sometimes present within the first or second decades, depending on the size of the CAG expansions. Disease onset during early infancy should point to a congenital form of ataxia or a metabolic disease. However, disorders associated with defective DNA repair, IOSCA, ARSACS, and several others, often present in the first years of life. An autosomal recessive transmission may be evident from the family pedigree, but it is not true in many instances. In sporadic cases, a consanguineous marriage or parental origin from an isolated area may be clues to AR inheritance. Affected members in two generations may be exceptionally found in autosomal recessive disorders with a pseudodominant pattern of inheritance. Conversely, incomplete penetrance or false paternity

may explain apparent absence of vertical transmission in dominant disorders. Excluding Friedreich ataxia and ataxia–telangiectasia, all the autosomal recessive cerebellar ataxias are rare, but their prevalence may be higher in countries where consanguineous marriages are frequent. The rarity of these diseases and the clinical variability among families makes it difficult to recruit enough patients to perform linkage studies. They have been possible in large consanguineous families or in genetic isolated populations. Cerebellar ataxia may present in variable combination with signs of degeneration of the long ascending and descending pathways, peripheral neuropathy, mental retardation, ocular features, hearing loss, extrapyramidal symptoms, endocrine dysfunction, and other features. Cosegregation of the associated features should be checked carefully to define the disease phenotype. A peculiar sign or pattern can sometimes be useful to make a specific diagnosis. MRI and some biochemical tests may be also of help. Molecular analysis is the gold standard when the genetic cause has been identified. Friedreich ataxia, ataxias associated with defective DNA repair, metabolic and mitochondrial disorders, and congenital ataxias are treated in other chapters. A pathogenetic classification of the remaining autosomal recessive forms is not feasible yet and we will follow a clinical scheme. A list of abbreviations is provided in Table 21.1.

EARLY-ONSET CEREBELLAR ATAXIA WITH RETAINED TENDON REFLEXES In 1893, Marie collected from the literature a group of four families affected by a form of hereditary ataxia clinically distinct from Friedreich ataxia due to the presence of brisk tendon reflexes. Onset age was variable;

*Correspondence to: Giuseppe De Michele, MD, Dipartimento di Scienze Neurologiche, Universita` “Federico II”, Via Pansini 5, I-80131 Napoli, Italy. Tel: þ39 081 7463711, Fax: þ39 081 5463663. E-mail: [email protected]

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Table 21.1 List of abbreviations ARCA ARSACS ARSAL AVED CAMOS CCFDN DIDMOAD EOCA EPM1 EPM2 FARR IOSCA KSS MERRF MSS NARP PEHO PMA PME SANDO SCAN1

Autosomal recessive cerebellar ataxia Autosomal recessive spastic ataxia of Charlevoix–Saguenay Autosomal recessive spastic ataxia with frequent leukoencephalopathy Ataxia and isolated vitamin E deficiency Cerebellar ataxia with mental retardation, optic atrophy, and skin abnormalities Congenital cataracts, facial dysmorphism, and neuropathy Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness Early-onset cerebellar ataxia with retained tendon reflexes Unverricht–Lundborg disease Lafora disease Friedreich ataxia with retained tendon reflexes Infantile-onset spinocerebellar ataxia Kearns–Sayre syndrome Myoclonic epilepsy with ragged-red fibers Marinesco–Sj€ogren syndrome Neuropathy, ataxia, and retinitis pigmentosa Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy Progressive myoclonic ataxia Progressive myoclonic epilepsy Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Spinocerebellar ataxia with axonal neuropathy

transmission was autosomal recessive in two families (Fraser, 1880; Nonne, 1891) and autosomal dominant in the remaining two (Brown, 1892; Klippel and Durante, 1892). The family described by Fraser comprised one brother and one sister with childhood-onset ataxia, strabismus, and optic atrophy in one. Nonne described three male patients in whom the onset of the disease varied from 10 to 29 years of age. The patients showed both optic atrophy and mental deficiency. Subsequently, the eponym “Marie’s hereditary ataxia” came into use to indicate hereditary forms of ataxia, with variable onset age and inheritance, retained or increased tendon reflexes, and usually some degree of spasticity. This term was criticized by Holmes (1907a) and Greenfield (1954) since the families described by Marie were clinically, genetically, and pathologically heterogeneous. Besides Marie’s cases, several patients with earlyonset autosomal recessive ataxia with retained tendon reflexes have been described (Burgess, 1892; Hodge, 1897; Sinkler, 1906; Harris, 1908; S€ oderbergh, 1910; Fickler, 1911; Sherman, 1934; Hogan and Bauman, 1977).

Additional features were present in some cases, such as hand amyotrophy (Hodge, 1897), optic atrophy (Hogan and Bauman, 1977), and mental deficiency (Fickler, 1911; Hogan and Bauman, 1977). Cerebellar atrophy was present in all the available postmortem examinations. The autopsy of one of the two patients reported by Fraser (1880) showed a small cerebellum with thinned cerebellar cortex and reduced number of Purkinje cells. The spinal cord was normal. Nonne (1891) reported postmortem findings from two of his patients, describing a small brain and spinal cord with a disproportionately small cerebellum and brainstem. The cerebellum and the spinal cord did not show any microscopical abnormality. The autopsy of one of the two patients reported by Fickler (1911) showed atrophy of the cerebellum, affecting mainly the hemispheres, and more on the upper than the lower surface. Microscopy showed loss of Purkinje cells, thinning of the granular layer, atrophy of the dentate nucleus, thinned nuclei of the pons, and loss of transverse fibers. The medullary olives were small. No tract degeneration was observed in the spinal cord. More recent postmortem studies are lacking. Harding in 1981 described 20 patients with progressive cerebellar ataxia, developing within the first two decades, dysarthria, pyramidal weakness, and retained/ increased tendon reflexes. The disease was sporadic in 16 cases, and present in other siblings in four. Harding labeled this disorder “early-onset cerebellar ataxia with retained tendon reflexes” (EOCA; MIM 212895), differentiating it from Friedreich ataxia based on preservation of knee jerks, a better prognosis, and absence of severe skeletal deformities, cardiomyopathy, optic atrophy, and diabetes mellitus. Among the early-onset inherited ataxias, EOCA is the second most common form, after Friedreich ataxia, representing 9–14% of all index cases (Harding, 1984; Filla et al., 1992). Prevalence ratio is between 0.8 and 1.5  105 in Europe (Polo et al., 1991; Filla et al., 1992; Chio` et al., 1993). EOCA is a genetically and phenotypically heterogeneous clinical entity. The segregation ratio was 0.15 in Harding’s series (1981), 0.16 in ours (Filla et al., 1990), and 0.11 in that reported by Klockgether et al. (1991), suggesting that not all the cases are of autosomal recessive inheritance. Non-genetic phenocopies or new dominant mutations are other possible explanations. Preponderance of males, observed in most series, is a hint at X-linked recessive inheritance in some cases (Harding, ¨ zeren et al., 1989; Filla et al., 1990; Klockgether 1981; O et al., 1991). The consanguinity rate ranges from 15% to ¨ zeren et al., 1989; Filla 40% in Europe (Harding, 1981; O et al., 1990; Klockgether et al., 1991) and is higher in North African families (Sridharan et al., 1985; Marzouki et al.,

OTHER AUTOSOMAL RECESSIVE AND CHILDHOOD ATAXIAS 345 2001). The distribution of onset age was different from The overall clinical picture was that of a cerebellar the normal one and onset age significantly varied betsyndrome, associated with signs of corticospinal ween families (Filla et al., 1990). These findings favor impairment (extensor plantar response and/or brisk tenthe hypothesis of genetic heterogeneity within EOCA. don jerks associated with increased tone) in two-thirds Advances in molecular genetics have partially eluciof the patients. Both cerebellar and corticospinal signs dated the EOCA syndrome. Seven out of our fifty (14%) were more severe in the lower than upper limbs. Clinical patients with the EOCA phenotype had the Friedreich signs of peripheral neuropathy (decreased vibration ataxia mutation. Another identified cause of spastic ataxia sense and decreased/absent ankle jerks) were present in is autosomal recessive spastic ataxia of Charlevoix– one-third of the patients. Progression was slow, with a Saguenay (ARSACS), first identified in French-Canadian median time to confinement to wheelchair of 22 years populations and associated with mutations in the SACS from disease onset (Klockgether et al., 1998). gene (Engert et al., 2000). In our series, it represents 4% Neurophysiological investigations demonstrated a of the cases with EOCA phenotype. Infantile-onset spinomainly sensory axonal neuropathy in 50% of the cerebellar ataxia (IOSCA), a severe childhood form patients. The abnormalities included a severe reduction hitherto identified only in Finnish families, is caused by a of the sensory potential amplitudes and slight slowing mutation in the C10orf2 gene (Nikali et al., 2005). No loci of sensory and motor conduction velocities. The presor genes have so far been identified in the remaining ence of peripheral neuropathy was not related to patients. In the interim, the diagnosis of EOCA still disease duration and severity (Santoro et al., 1992). remains useful to indicate a clinical category defined by The findings at sural nerve biopsy varied from normal the following diagnostic criteria: 1) autosomal recessive to a marked loss of large myelinated fibers with inheritance or sporadic occurrence; 2) early-onset (< 25 unimodal distribution of the axon diameters of the years); 3) progressive cerebellar ataxia; 4) retained knee remaining fibers. Short-latency central somatosensory jerks; 5) absence of associated features such as pigmenevoked potentials were abnormal after stimulation of tary retinal degeneration, cataract, hypogonadism, and the tibial nerve in most patients. Brainstem auditory myoclonus; 6) exclusion of a known etiology. evoked potentials were abnormal in about two-thirds In our personal series, half of the patients were of the patients. Central motor and visual evoked potensporadic and half had an affected sib. Consanguinity tials were abnormal in half of the patients. was present in 24% of marriages. Onset age ranged On MRI, cerebellar atrophy was a frequent, but not from 2 to 25 years, with two peaks, at 1–3 and 12–15. obligatory, finding (Wu¨llner et al., 1993; Ormerod Mean onset age  SD was 10.4  8.1 years in our series. et al., 1994; De Michele et al., 1995). It was usually Gait ataxia heralded the disease in the majority of cases. slight, but could be severe in some instances, particuOther rarer presenting symptoms were dysarthria, larly at the level of the cerebellar vermis. Half of the tremor, lower limb weakness, and clumsiness. patients also showed atrophy of the brainstem and/or Gait and stance ataxia were present in all cases and the cervical spinal cord. Rarely, cortical atrophy or T2 other cerebellar signs were very common. Eye movement hyperintense areas in the white matter could be abnormalities such as jerky smooth pursuit, dysmetric observed. Single-photon emission computed tomograsaccades, and nystagmus in the lateral gaze were almost phy (SPECT) with 99mTc-HMPAO showed cerebellar constant. Gaze paralysis was absent and saccade velocity hypoperfusion in most patients and cortical hypoperwas usually normal. Dysarthria, usually mild to moderate, fusion in half of them (De Michele et al., 1998). Global was frequent. Dysphagia, usually for liquids, affected hypometabolism, more evident in the thalamus and one-third of the patients. Brisk knee jerks, increased lower cerebellum, has been demonstrated by FDG-PET in limb tone, and proximal lower limb weakness were prestwo sibs with EOCA and cognitive impairment (Mielke ent in about half of the patients. Ankle jerks were brisk et al., 1998). in one-third, weak or absent in another third. Plantar As already mentioned, preservation of knee jerks is responses were extensor in one-third. Two-thirds of the the clinical hallmark which separates EOCA from typipatients had decreased vibration sense at the external cal Friedreich ataxia. However, about 10% of Friedreich malleolus, slight scoliosis, and pes cavus. ataxia patients have retained tendon reflexes (FARR). Non-progressive mental deficiency, slight distal The presence of hypertrophic cardiomyopathy or diabeamyotrophy, and urinary urgency may occur. Head tes strongly suggests this diagnosis even in patients titubation, seizures, psychosis, hypoacusis, dystonia, with retained tendon reflexes. Conversely, severe cerehand amyotrophy, and perioral fasciculations were bellar atrophy is found only in EOCA. The molecular rare. No patient had optic atrophy, retinal degeneration, test for the Friedreich mutation can easily differentiate diabetes, or echocardiographic findings of hypertrophic EOCA from Friedreich ataxia and should be performed cardiomyopathy. in all patients with EOCA phenotype.

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EOCA should be also differentiated from metabolic disorders. Patients with ataxia and isolated vitamin E deficiency (AVED) may retain lower limb reflexes. Head titubation and fasciculations of the tongue point to the diagnosis of AVED, which is confirmed by low levels of serum vitamin E. Storage diseases should also be considered in the differential diagnosis, and assays for hexosaminidase A, beta-galactosidase, and arylsulfatase A performed in selected cases. Early-onset cerebellar ataxia, followed by development of upper and lower motor neuron signs, has been described in patients with hexosaminidase A deficiency. Dysarthria, ataxia, intention tremor, and corticospinal signs have been described in a family with beta-galactosidase deficiency (Chakraborty et al., 1994). Cerebellar signs may be found in juvenile cases of metachromatic leukodystrophy. Mental deterioration, abnormal behavior, corticospinal signs, and dystonia characterize the clinical picture. Early-onset ataxia with pyramidal signs, mental impairment, supranuclear vertical gaze paralysis, dystonia, and seizures may be caused by Niemann-Pick type C. Lipid-laden macrophages (foam cells) are present in the bone marrow aspiration and liver biopsy specimen. Impaired esterification of exogenous cholesterol is present in cultured fibroblasts. Adrenomyeloneuropathy presents with spastic paraplegia and distal sensory loss in affected males, but cerebellar signs may be prominent and atrophy of the cerebellum and brainstem has been reported (Ohno et al., 1984). Hypoadrenalism and MRI findings of diffuse demyelination may lead to the diagnosis, which is confirmed by measurement of verylong-chain fatty acid, showing elevated C 26:0 levels in plasma and fibroblasts. Ataxia–telangiectasia and the other ataxias associated with defective DNA repair are often associated with oculomotor apraxia, choreoathetosis, areflexia due to axonal neuropathy, and typical serologic abnormalities. Assay of sex hormones and gonadotrophins may be useful in differentiating EOCA from ataxia with hypogonadism, in which corticospinal signs are frequent. The differential diagnosis between EOCA and forms of hereditary spastic paraplegia complicated by a cerebellar syndrome, such as SPG2 and SPG7, may be difficult. If examination of other affected relatives and molecular genetic testing are not helpful, the diagnosis relies only on the predominance of the corticospinal or cerebellar features. Mild cerebellar signs may occur in Troyer (SPG20) and Mast (SPG21) syndromes, both described in Amish people, which have peculiar recognizable phenotypes. ARSACS is characterized by childhood onset, marked spasticity, distal amyotrophy, cerebellar signs, and slow progression after 20 years. A prominent

retinal nerve fiber layer in the optic fundi is a peculiar, but not constant, sign. Genetic testing is diagnostic. Non-hereditary ataxias can present with an EOCAlike phenotype. MRI can demonstrate platybasia and basilar impression, conditions where spastic quadriparesis and cerebellar signs may occur. One concern in the differential diagnosis of a progressive gait disorder with ataxia and spasticity is multiple sclerosis. T2- and PD-weighted images, and gadolinium use are very helpful, although patients with primary progressive multiple sclerosis have fewer MRI lesions and less frequent enhancing T1-weighted lesions. Malabsorption, irondeficiency anemia, and detection of antigliadin and anti-endomysial antibodies points to a diagnosis of celiac disease, which may cause a progressive and treatable cerebellar syndrome. Patients with cerebellar ataxia and retained reflexes, with sporadic occurrence and unknown etiology, may present after 25 and before 40 years. It is a matter of debate if they should be diagnosed as EOCA or as idiopathic late-onset cerebellar ataxia (ILOCA).

AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF CHARLEVOIX^SAGUENAY Autosomal recessive spastic ataxia of Charlevoix– Saguenay (ARSACS; MIM 270550) was first described in 1978 in patients originating from a genetic isolate in the Charlevoix and Saguenay regions of Quebec, Canada (Bouchard et al., 1978). More than 200 families have been identified in this area with a carrier frequency of 1/22 (De Braekeleer et al., 1993; Bouchard et al., 1998). The responsible gene (SACS) has been mapped to chromosome 13q11-12 (Bouchard et al., 1998; Richter et al., 1999), and it encodes sacsin, a protein of still unknown function (Engert et al., 2000). A founder effect has been demonstrated by the identification of a SACS homozygous single base deletion (6594delT) in about 96% of the alleles. In compound heterozygotes, the 6594delT mutation is associated with an R1752X mutation or the mutation could not be identified. Both mutations lead to protein truncation. Engert et al. (2000) found that the 11,487-bp open reading frame of SACS is encoded by a single gigantic exon spanning 12,794 bp. In the recent versions of Genome Project gene predictions, a number of smaller exons are reported upstream of the original SACS ORF. The number of new exons and transcription initiation site are yet to be established. SACS maps to a region of mouse chromosome 1 where the recessive tumbler mutation has been mapped (Dickie, 1965). Sacsin is expressed in a variety of tissues, including the central nervous system, mainly the cerebral cortex, the granular cell layer of the cerebellum, and the hippocampus

OTHER AUTOSOMAL RECESSIVE AND CHILDHOOD ATAXIAS (Engert et al., 2000). Secondary structure prediction indicates that the C-terminal portion of sacsin contains a DnaJ motif, which is found in proteins that interact in chaperone-mediated protein folding. Moreover, two large sacsin sequences are similar to the N-terminal of the Hsp90 class of heat-shock proteins, which act as molecular chaperones. These data suggest that sacsin may function in chaperone-mediated protein folding. A bioinformatics study showed that sacsin has a HEPN (higher eukaryotes and prokaryotes nucleotide-binding domain) at the C-terminus (Grynberg et al., 2003). Sacsin is the only higher vertebrate protein known to contain this domain, which might be involved in nucleotide binding. A postmortem study of a 21-year-old man (Richter et al., 1993) showed atrophy of the superior cerebellar vermis, especially in the anterior structures (central lobule and culmen), where Purkinje cells were absent. The molecular and granular layers were thin; in the spinal cord there was loss of myelin staining in the lateral corticospinal tracts and dorsal spinocerebellar tracts. Abnormalities were more pronounced in a 59-year-old man, and extended to the hippocampus, neocortex, basal nucleus of Meynert, globus pallidus, thalamus, dentatus nucleus, and posterior columns (Bouchard et al., 2000). Sural nerve biopsy showed loss of large myelinated fibers; there was increased variability of internodal length on nerve teasing. Patients present with early-onset spasticity, usually within the second year of life (Bouchard et al., 1978; Richter et al., 1993). In the early disease stage, gait ataxia is mild with a tendency to fall and clumsiness in running. Tendon reflexes are increased, often with ankle clonus and extensor plantar response. However, progressive involvement of the peripheral nerve results in the disappearance of ankle jerks around the age of 25 years. Horizontal gaze nystagmus is constant and smooth pursuit is jerky. Speech is slurred in childhood and becomes explosive in adulthood. Dysdiadochokinesia is early; upper limb dysmetria occurs later. Distal amyotrophy may be an early feature, but usually appears later (Fig. 21.1). Vibration sense is decreased early, and it declines further as the disease progresses. Pes cavus and clawing of the toes develop progressively in the first two decades in most patients. Urgency and incontinence are late symptoms. Patients can show learning difficulty, and non-verbal IQ is below normal limits. Hand tremor, facial grimaces, dystonic postures, and dysphagia are occasionally seen. Generalized seizures are reported in a small percentage of patients. A peculiar abnormality at funduscopy is the presence of prominent myelinated fibers radiating from the optic disk and embedding the retinal blood vessels, mainly in the papillomacular bundle area. Visual acuity, however, is normal.

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The worsening of the spasticity and of the cerebellar syndrome and the appearance of signs of axonal polyneuropathy account for the disease progression, mean age at becoming wheelchair-bound being 41 years. Electroencephalographic abnormalities occur in more than 60% of cases, with bursts of generalized slow waves of subcortical origin in most patients and epileptiform activity in a few of them. Electromyography shows denervation and nerve conduction studies reveal absence of sensory action potentials, increased distal motor latency, and moderate to marked reduction of motor velocity (Bouchard et al., 1979; Peyronnard et al., 1979). Somatosensory, brainstem auditory, and pattern reversal visual evoked potentials are often abnormal. MRI shows constant and early atrophy of the superior vermis; atrophy of the spinal cord and, late in the disease course, of the cerebrum (Fig. 21.1). After mapping of the ARSACS locus, one Tunisian (Mrissa et al., 2000) and two Turkish families (Gu¨cu¨yener et al., 2001) showed linkage to the same chromosomal region, and after gene identification, missense and nonsense mutations of the SACS gene have been found in Tunisia (El Euch-Fayache et al., 2003), Italy (Criscuolo et al., 2004; Grieco et al., 2004), Japan (Ogawa et al., 2004; Hara et al., 2005; Shimazaki et al., 2005; Yamamoto et al., 2005), Turkey (Richter et al., 2004), and Spain (Criscuolo et al., 2005). The phenotype of these patients is comparable to that identified in Quebec, except for some minor differences. Age at onset may be later, up to 20 years. Retinal myelinated fibers are rare; cognitive impairment more frequent. Early loss of ankle reflexes has been reported by Mrissa et al. (2000); Shimazaki et al. (2005) noted extensor plantar responses in the absence of spasticity and hyperreflexia. Mutations in the SACS gene have been excluded in families with an ARSACS-like phenotype and a novel locus, SAX2, has been mapped to chromosome 17p13 in a consanguineous Moroccan kindred (Bouslam et al., 2007).

AUTOSOMAL RECESSIVE SPASTIC WITH FREQUENT LEUKOENCEPHALOPATHY Autosomal recessive spastic ataxia with frequent leukoencephalopathy (ARSAL) is another form of spastic ataxia identified in Quebec. Mean age at onset is 15 years. Other disease features are dysarthria, nystagmus, scoliosis, dystonia, urinary urgency, and mild cognitive impairment. Brain MRI shows constant cerebellar atrophy, in some cases associated with cortical atrophy, leukoencephalopathy, and corpus callosum thinning. The disease locus has been mapped to chromosome 2q33-34 (Thiffault et al., 2006).

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Fig. 21.1. Atrophy of intrinsic hand muscles (A), claw foot and hammertoes (B), T1-weighted sagittal magnetic resonance imaging scan showing cerebellar (C), and spinal atrophy (D) in a patient affected by ARSACS. (From Garcia et al. 2008 and Criscuolo et al. 2005.)

AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF THE BEAUCE A form of autosomal recessive cerebellar ataxia (ARCA-1; MIM 610743) has been identified in the Beauce region of Quebec. Onset is over 25 years, progression slow, and neuropathy absent. Minor oculomotor abnormalities and brisk tendon reflexes have been found in some patients. Marked cerebellar atrophy is revealed by MRI. Linkage to chromosome 6q has been demonstrated and seven mutations have been identified in the SYNE1 gene, which encodes a protein containing multiple spectrin repeats that is expressed predominantly in the cerebellum. The protein may have a role in myonuclear anchorage (Dupre´ et al., 2007).

Another form of autosomal recessive cerebellar ataxia (ARCA-2; MIM 612016), caused by mutations in the ADCK3 gene, has been associated with CoQ10 deficiency and may be classified within the mitochondrial ataxias.

CEREBELLAR ATAXIAWITH HYPOGONADISM Cerebellar ataxia with hypogonadism was first reported by Gordon Holmes (1907b) in four siblings (three males, one female) with adult-onset cerebellar ataxia, head and upper limb tremor, and brisk reflexes. The three brothers had poorly developed genitalia and scanty body hair. Postmortem examination of a case showed atrophy

OTHER AUTOSOMAL RECESSIVE AND CHILDHOOD ATAXIAS of the superior cerebellar cortex and inferior olives. The pons and medulla were also slightly reduced in size. Purkinje cells and, to a lesser extent, granule cells were lost. According to Holmes’ description, the parents were normal, suggesting a recessive nature of the gene. Nevertheless, the term “Holmes type” of cerebello-olivary degeneration has been used to label dominantly inherited ataxias in the absence of genital abnormalities, purely on the basis of similar pathologic findings. After Holmes’ original report, about 100 similar cases have been described. Variability of onset age, neurologic features, and endocrine findings suggests that cerebellar ataxia with hypogonadism is a heterogeneous syndrome. Its etiology has not been elucidated yet. Mutations in the GnRH receptor gene have been excluded in a family (Seminara et al., 2002). Partial deficiency of muscle cytochrome c oxidase has been shown in one case (De Michele et al., 1993). Two brothers with late-onset CoQ10 deficiency, cerebellar ataxia, myopathy, and hypergonadotropic hypogonadism have been described (Gironi et al., 2004). Postmortem examination of the brain has been performed only in a few cases. Altschul and Kotlowski (1956) reported cerebello-olivary degeneration with calcification of the globus pallidus and putamen. Matthews and Rundle (1964) described cerebello-olivary degeneration, involvement of tracts in the spinal cord and brainstem, and diffuse loss of myelinated fibers in the cerebrum, cerebellum, and thalamus. We described a small cerebellum (Fig. 21.2), with atrophy most marked in the vermis, shrinkage of the pons, almost complete disappearance of Purkinje cells, and neuronal loss in the granular layer and the inferior olives (De Michele et al., 1990). Onset of ataxia may occur from early childhood to the fourth decade, with a mean around 24 years. Frequent features associated with cerebellar symptoms include corticospinal signs, dementia, peripheral axonal

Fig. 21.2. Cerebellar atrophy in a patient with hypogonadotropic hypogonadism, compared to a control (right). (Courtesy of Prof. F. D’Armiento, Federico II University, Naples, Italy.)

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neuropathy, and deafness. Brain imaging reveals cerebellar atrophy and, in some instances, cerebral white matter abnormalities (Ohara et al., 1992; De Michele et al., 1993; Seminara et al., 2002). In the majority of cases, the gonadal deficiency is of hypogonadotropic origin (MIM 212840), but primary hypergonadotropic hypogonadism (MIM 605672) has also been reported in a small number of cases (Amor et al., 2001). Hypogonadotropic hypogonadism may arise from either hypothalamic or pituitary dysfunction. Repeated stimulation with luteinizing hormone-releasing hormone (LHRH) may be useful to distinguish between hypothalamic and pituitary origin of the hypogonadism (Seminara et al., 2002). Pituitary dysfunction is more frequent, whereas primary hypothalamic disturbance has been shown in a minority of cases (Berciano et al., 1982). Hypogonadotropic and hypergonadotropic hypogonadism must be considered distinct forms, whereas the hypothalamic or pituitary variants could depend on a different stage of the degenerative process and may be found in different members of the same family (Seminara et al., 2002). Boucher—Neuhäuser syndrome (MIM 215470) is a very rare autosomal recessive disorder, characterized by the triad of spinocerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism. Onset of symptoms varies from adolescence to early adulthood. The origin of the gonadic defect is probably pituitary (Fok et al., 1989) and other endocrine abnormalities have been described, such as impaired growth hormone (GH) response to GH-releasing factor, insulin-induced hypoglycaemia (Tojo et al., 1995), and hypocalciuric hypercalcemia (Ichinose et al., 1995). Mental decline, short stature, and hypersegmented neutrophils were associated features in a Jordanian family (Jbour et al., 2003). One case has been associated with complex I mitochondrial respiratory chain deficiency and a 5.5-kb mtDNA single deletion in skeletal muscle (Barrientos et al., 1997). Richards—Rundle syndrome (MIM 245100) is a very rare disorder, characterized by childhood-onset ataxia, hearing loss, mental deterioration, muscle wasting, hypergonadotropic hypogonadism, and ketoaciduria. Inheritance is autosomal recessive. Hypergonadotropic hypogonadism is a feature of Marinesco–Sj€ogren syndrome (Skre et al., 1976) and has been reported in males with Wolfram syndrome and in females with IOSCA. Cerebellar ataxia and hypogonadotropic hypogonadism due to a pituitary defect have been described in association with mitochondrial myopathy and myoclonus (Fitzsimons et al., 1981; Toscano et al., 1995). The association of Klinefelter syndrome and cerebellar ataxia has also been reported (Hecht and Ruskin, 1960).

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CEREBELLAR ATAXIAWITH OCULAR FEATURES Non-specific ocular manifestations, such as optic atrophy and retinitis pigmentosa, have been reported in association with cerebellar ataxia. Mental retardation or dementia, deafness, pyramidal signs, and peripheral neuropathy may also be present. More specific is the association of cerebellar ataxia and cataract, which points to the Marinesco–Sj€ ogren syndrome.

Cerebellar ataxia and optic atrophy Optic atrophy, often present in the late stages of Friedreich ataxia, may be associated with other autosomal recessive ataxic disorders. The first recognized entity is Behr syndrome (MIM 210000), a probably heterogeneous entity with onset in early childhood, characterized by ataxia, optic atrophy, spasticity, and mental retardation. Pizzatto and Pascual-Castroviejo (2001) found moderate to marked cerebellar atrophy in five cases in which MRI was performed. Bomont et al. (2000) described the association of early-onset recessive ataxia and subsequent optic atrophy and hearing impairment (MIM 271250) in two patients from an Israeli consanguineous family and mapped the disease locus to chromosome 6q21-q23. Infantile-onset spinocerebellar ataxia (IOSCA; MIM 271245) is a rare autosomal recessive disorder of the genetically isolated Finnish population (Koskinen et al., 1994). The disease has been mapped to a locus on chromosome 10q24 (Nikali et al., 1997). Two causative point mutations have been identified in the gene C10orf2, which encodes Twinkle, an mtDNA-specific helicase, and a rarer splice variant, Twinky (Nikali et al., 2005). Both have a so-far unknown function. Depletion of mtDNA has been recently shown in the brain and liver of IOSCA patients, suggesting that IOSCA is a new member of the mtDNA depletion syndromes (Hakonen et al., 2008). All the patients were homozygous for a founder point mutation (1708A!G), except a compound heterozygote with a silent mutation (1472C!T), affecting the protein transcriptional level. The presence of two different mutations suggests that IOSCA might be not restricted to Finland. Different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions, a neuromuscular disorder sharing a spectrum of symptoms with IOSCA. Pathological findings show progressive degeneration of the cerebellum, brainstem, and spinal cord. The disease has a very early onset, at age 9–18 months, and rapid progression comprising, besides ataxia, epilepsy, athetosis, optic atrophy, ophthalmoplegia, hearing loss, sensory neuropathy with areflexia, primary hypergonadotropic

hypogonadism in females, and reduced mental capacity in some patients (Koskinen et al., 1994). The main finding on imaging is cerebellar atrophy. Progressive loss of myelinated fibers has been observed in the sural nerve. Wolfram syndrome (MIM 222300), also known by the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an autosomal recessive disorder, with onset of symptoms usually in the first decade of life. Loss-of-function mutations of the WFS1 gene on chromosome 4p have been found (Strom et al., 1998). The gene codes for wolframin, a transmembrane glycoprotein that localizes primarily in the endoplasmic reticulum. Wolframin is ubiquitously expressed, with highest levels in the brain, pancreas, and heart. Another locus for the disorder has been mapped to 4q (WFS2). Wolfram syndrome is characterized by a number of neurologic symptoms, including ataxia, myoclonus, central respiratory failure, hearing loss, peripheral neuropathy, mental retardation, and psychiatric illnesses. MRI may show marked brainstem atrophy. Ataxia and optic atrophy may also coexist in congenital ataxias, such as cerebellar ataxia with mental retardation, optic atrophy, and skin abnormalities (CAMOS) and progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO), and in several metabolic and mitochondrial disorders.

Cerebellar ataxia and retinitis pigmentosa Posterior column ataxia with retinitis pigmentosa (MIM 609033) is an autosomal recessive disorder with onset in childhood, concentric contraction of the visual fields, sensory ataxia, areflexia, and proprioceptive loss. Higgins et al. (1999) mapped the disease locus (AXPC1) to chromosome 1q31-q32. Ataxia and retinitis pigmentosa are also found in metabolic diseases such as abetalipoproteinemia; ataxia and isolated vitamin E deficiency (AVED); congenital disorder of glycosylation type Ia; Refsum disease; neuropathy, ataxia and retinitis pigmentosa (NARP); CoQ10 deficiency; and Kearns–Sayre syndrome (KSS). Ophthalmologic examination in neuronal ceroid lipofuscinoses with infantile and juvenile onset reveals optic atrophy and retinal and macular degeneration.

Cerebellar ataxia and cataracts Marinesco—Sj€ogren syndrome (MSS; MIM 248800) is a rare autosomal recessive multisystem disorder, clinically characterized by cataracts, cerebellar ataxia, myopathy, and growth and mental retardation. Clinical and genetic heterogeneity has been demonstrated in MSS. In pure MSS families, a locus has been mapped on chromosome 5q31 (Lagier-Tourenne et al., 2003) and pathogenetic mutations have been identified in the

OTHER AUTOSOMAL RECESSIVE AND CHILDHOOD ATAXIAS SIL1 gene. SIL1 encodes a nucleotide exchange factor for the heat-shock protein 70 chaperone HSPA5, which is a key regulator of the main functions of the endoplasmic reticulum (Anttonen et al., 2005; Senderek et al., 2005). The types of mutations suggest loss of function of SIL1, and the disturbed SIL1–HSPA5 interaction could lead to decreased protein synthesis or misfolding in the endoplasmic reticulum, or to cell degeneration subsequent to accumulation of unfolded protein. Autopsy findings of MSS are heterogeneous. They vary from severe cerebellar atrophy to diffuse brain atrophy with or without minimal evidence of cerebellar involvement. Histology shows neuronal loss in the cerebellar cortex with vacuolated or binucleated Purkinje cells. Besides cerebellar atrophy, morphological changes of the pituitary gland (small anterior, and absence of posterior pituitary bright spot) seem to be common. Both myopathic and denervation changes have been reported at muscle biopsy. The ultrastructural observations of a dense membranous structure associated with nuclei in some muscle biopsies have not been constantly reported. Onset of MSS may be congenital, or may occur in infancy or early childhood. The phenotype is characterized by cataracts from infancy, cerebellar ataxia of variable severity, nystagmus, dysarthria, hypotonia, mild to severe mental retardation, short stature, chronic myopathic changes at EMG and muscle biopsy, and elevated serum CK. Additional reported features are strabismus, skeletal deformities (kyphoscoliosis, contractures, short metatarsal and metacarpals, bulging sternum), and hypergonadotropic hypogonadism. Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) syndrome (MIM 604168), an autosomal recessive disorder reported in Bulgarian Gypsies, maps to 18q23-qter. Varon et al. (2003) showed that CCFDN is caused by a single founder mutation in intron 6 of the CTDP1 gene. The gene encodes the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery. There is genetic identity between CCFDN and a MSS subtype with demyelinating peripheral neuropathy and myoglobinuria (Merlini et al., 2002). Patients with CCFDN exhibit congenital cataracts, microcornea, and delayed psychomotor development, followed by predominantly motor peripheral neuropathy with skeletal deformities, short stature, and hypogonadotropic hypogonadism in females. Possible neurological features are mild ataxia, upper limb postural tremor, chorea, and corticospinal signs. Ataxia—microcephaly—cataract syndrome (MIM 208870), described in a highly inbred Arab family, is another form which partially resembles MSS. Cataract is also present in cerebrotendinous xanthomatosis.

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CEREBELLAR ATAXIAWITH DEAFNESS Over 400 forms of syndromic hearing loss have been described and cerebellar ataxia is present in a few of them. The Lichtenstein—Knorr syndrome is characterized by progressive hearing loss, unsteady gait, and dysarthria. According to Harding (1984), the originally described patients might have been affected by Friedreich ataxia. The clinical features of the Berman syndrome (MIM 208850) are infantile-onset progressive ataxia, hearing loss, mental retardation, and signs of both upper and lower motor neuron involvement. Mental retardation, cardiomyopathy, and skin pigmentary changes are present in Jeune—Tommasi disease (MIM 208750). The triad of spinocerebellar ataxia, blindness, and deafness (MIM 271250) described by Bomont et al. (2000) has already been mentioned. Hypoacusis may be a feature of Friedreich ataxia, IOSCA, Refsum disease (MIM 266500), and ataxia with hypogonadism. The ataxia associated with retinitis pigmentosa and congenital deafness in Usher syndrome (MIM 276900) is likely of vestibular origin.

CEREBELLAR ATAXIAWITH MYOCLONUS In 1921, Ramsay Hunt described the association of ataxia and myoclonus in six patients. Onset of ataxia was in early childhood and preceded the development of myoclonus and intention tremor in two twin boys. The other four patients were sporadic and presented with myoclonus and epilepsy, whereas progressive cerebellar ataxia developed in adult life. Autopsy of one twin showed degeneration of the spinocerebellar tracts and posterior columns, dentate nuclei, and superior cerebellar peduncles. The use of the term “Ramsay Hunt syndrome” to define the association of ataxia and myoclonus, sometimes combined with seizures, has been criticized since it does not represent a specific entity; therefore, it should be replaced by the term progressive myoclonic ataxia (Marsden et al., 1990). Progressive myoclonic epilepsy (PME) and progressive myoclonic ataxia (PMA) share common causes. However, the majority of patients with PME can have a specific diagnosis in life, whereas that may be more difficult in patients with PMA. Five conditions account for most PME/PMA cases: Unverricht–Lundborg disease, Lafora disease, myoclonic epilepsy with ragged-red fibers (MERRF), neuronal ceroid lipofuscinoses, and sialidoses (Berkovic et al., 1986; Shahwan et al., 2005). Unverricht–Lundborg disease (EPM1; MIM 254800) is an autosomal recessive disorder whose locus (EPM1) has been mapped to 21q22.3. EPM1 results from mutations in the cystatin B gene (CSTB), which encodes for a cysteine protease inhibitor. A pathologically

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expanded dodecanucleotide repeat in the 50 untranslated region of the gene is the most frequent mutation responsible for the disease (Lalioti et al., 1997). Loss of inhibition of cysteine proteases, which are involved in the initiation of apoptosis, could lead to abnormal apoptosis and neurodegeneration. EPM1 is clinically characterized by onset at 6–15 years of age, stimulussensitive myoclonus, tonic-clonic seizures, cerebellar signs, mild dementia, and progressive course. A second locus has been mapped to the pericentromeric region of chromosome 12 (Berkovic et al., 2005). The recently identified causative gene, PRICKLE1, may be involved in planar cell polarity signaling during embryogenesis (Bassuk et al., 2008). Also, Lafora disease (MIM 254780) is genetically heterogeneous. Up to 80% of the families show linkage to the EPM2A locus (6q23-25) and several mutations have been described in the EPM2A gene, which encodes laforin (Minassian et al., 1998), a protein tyrosine phosphatase probably involved in translational regulation and protein folding. A second locus (EPM2B, 6p22.3) and gene (NHLRC1) encodes malin, a putative E3 ubiquitin ligase (Chan et al., 2003). EPM2 is transmitted as an autosomal recessive trait. Onset is usually during late childhood and adolescence. It is characterized by seizures and myoclonic jerks, severe cognitive impairment, and early death. There is abnormal accumulation of periodic acid-Schiff (PAS)-positive polyglucosans in the brain, leading to neuronal death. NHLRC1 and EPM2A may act together to protect neurons against polyglucosan accumulation. The presence of PAS-positive inclusion bodies on muscle and skin biopsies allows the diagnosis of Lafora disease (Fig. 21.3). The neuronal ceroid lipofuscinoses are a group of autosomal recessive diseases characterized by intralysosomal accumulations of lipopigments in the brain, eyes, and other tissues. They usually manifest during

Fig. 21.3. Red purple Lafora inclusion bodies in a sweat gland duct from an axillary skin biopsy (PAS þ hematoxylin stain). (Courtesy of Prof. F. Barbieri, Federico II University, Naples, Italy.)

childhood and adolescence, but very rarely also in young adults, and include infantile Santavuori disease (MIM 256730), late infantile Jansky–Bielschowsky disease (MIM 204500), juvenile Vogt–Spielmeyer disease (or Batten disease; MIM 204200), Kufs disease (MIM 204300), and other variants (MIM 256731, 600143, 601780). The main features are visual failure, with optic atrophy and macular degeneration, psychomotor regression, seizures, dysarthria, myoclonus, and cerebellar and extrapyramidal features. Sialidoses (MIM 256550), too, are autosomal recessive lysosomal disorders. Sialidosis type I (cherry-red spot myoclonus syndrome) is caused by deficiency of a-neuraminidase. It has juvenile or adult onset and its clinical features include action myoclonus, gradual visual failure, tonic-clonic seizures, ataxia, and a characteristic cherry-red spot in the fundus. Sialidosis type II, the more severe form, is an allelic disorder. The onset is from infantile to juvenile. It is clinically characterized by myoclonus, corneal opacities, coarse facial features, hepatomegaly, skeletal dysplasia, neuropathy, and dementia. Urine sialyloligosaccharides are useful for the diagnosis of sialidosis. The most common mutation in patients with MERRF is an A-to-G transition at nucleotide 8344 in the mitochondrial DNA gene MT-TK, which encodes tRNALys. MERRF is characterized by a variable onset age and almost constant presence of myoclonus, ataxia, dementia, and dysarthria. Tonic-clonic seizures, short stature, hearing loss, optic atrophy, and distal amyotrophy are frequent. Ragged-red fibers (RRF) are found in the muscle biopsy. Ekbom syndrome is a mitochondrial encephalomyopathy associated with the same heteroplasmic tRNA mutation as seen in MERRF. The syndrome consists of cerebellar ataxia, photomyoclonus, skeletal deformities, and lipoma. May–White syndrome (myoclonus, cerebellar ataxia, and deafness), originally described as dominant, is likely to be a mitochondrial disease. There are a few other disorders which may cause PMA. The myoclonus–nephropathy syndrome (MIM 254900), observed in French-Canadian patients, is an autosomal recessive syndrome with onset in the second decade of life. The clinical picture comprises severe progressive action myoclonus, dysarthria, ataxia, infrequent generalized seizures, and renal failure. Mutations in the POLG gene (MIM 607459) may cause an autosomal recessive progressive disorder characterized by migraine or epilepsy, ataxia, ophthalmoplegia, dementia, neuropathy, myoclonus, and tremor (Winterthun et al., 2005). MRI shows signal changes in the cerebellum, olives, occipital cortex, and thalami. COX-deficient fibers and multiple mtDNA deletions may be found at muscle biopsy. Dentatorubral–pallidoluysian atrophy (myoclonic epilepsy, dementia, ataxia, and choreoathetosis) shows

OTHER AUTOSOMAL RECESSIVE AND CHILDHOOD ATAXIAS 353 a dominant mode of inheritance. Celiac disease and Sensory neuropathy is a feature of spinocerebellar Whipple’s disease should also be considered as non-genetic ataxia with saccadic intrusions, also called SCA24 causes of PMA. (MIM 607317). The disorder has been described in five siblings and is characterized by progressive ataxia beginning in the third decade, horizontal macrosaccadic CEREBELLAR ATAXIAWITH oscillations, myoclonic jerks, corticospinal signs, axonal NEUROPATHY sensorimotor neuropathy, and mild pes cavus (Swartz Peripheral nerve involvement is one of the most frequent et al., 2002). features associated with cerebellar ataxia in autosomal recessive disorders. Peripheral neuropathy is constant CEREBELLAR ATAXIAWITH in disorders such as Friedreich ataxia, AVED, ataxias EXTRAPYRAMIDAL FEATURES associated with DNA repair defects, NARP, SANDO Parkinsonism and other extrapyramidal features may (sensory ataxic neuropathy, dysarthria, and ophthalmobe associated with ataxia in several late-onset degeneraparesis), and ARSACS, and it is frequent in EOCA and tive diseases, such as multiple system atrophy (MSA), many other ataxic syndromes. Here we consider four SCA2, Machado–Joseph disease (MJD/SCA3), SCA6, additional autosomal recessive disorders characterized SCA17, FXTAS, neuroferritinopathy, and prion disorby ataxia and neuropathy. ders. Conversely, such association is rare in early-onset Spinocerebellar ataxia with axonal neuropathy cases. (SCAN1; MIM 607250) has been described in a large Cerebellar ataxia has been described in association inbred Saudi Arabian family. The disease maps to with tremor and other parkinsonian features only in a 14q31-q32 and is caused by a homozygous missense few families, mostly from consanguineous marriages mutation in the TDP1 gene, coding for tyrosyl-DNA (Harding, 1984). Improvement after levodopa adminisphosphodiesterase (Takashima et al., 2002). The TDP1 tration has been reported in some patients. Both ataxia gene contains 17 exons, and is expressed ubiquitously and parkinsonism may be features of rare, complex, throughout the CNS and peripheral tissues. The enzyme autosomal recessive disorders, such as Chediak–Higashi is a member of the phospholipase D superfamily and is syndrome and SANDO. involved in repairing topoisomerase I–DNA covalent Cerebellar and extrapyramidal features can be found in complexes. TDP1 mutations are not a common cause autosomal recessive metabolic disorders, such as metaof recessively inherited ataxias in Japan. The losschromatic leukodystrophy, and in two disorders involving of-function mutations in TDP1 may cause SCAN1 by excess cerebral iron accumulation. Aceruloplasminemia interfering with DNA transcription or by inducing (MIM 604290) is an autosomal recessive disorder caused apoptosis in post-mitotic neurons. by mutation in the gene encoding ceruloplasmin (CP), The disease begins in the second decade and is which is essential for iron homeostasis and neuronal characterized by progressive ataxia, areflexia, decreased survival (Harris et al., 1995). Pathological studies show iron vibration sense, distal muscular atrophy, pes cavus, hyperdeposition in the liver, pancreas, retina, basal ganglia, and cholesterolemia, and borderline hypoalbuminemia. The substantia nigra, with associated neuronal dropout and neurophysiologic findings are those of an axonal motor spongiform degeneration. The disease begins between and sensory neuropathy. MRI shows cerebellar atrophy, the ages of 30 and 50 years and is characterized by retinal sometimes associated with mild cerebral atrophy. degeneration, ataxia, dysarthria, dementia, extrapyramiLaryngeal abductor paralysis with cerebellar ataxia dal symptoms (blepharospasm, grimacing, facial and neck and motor neuropathy (MIM 606183) has been reported dystonia, tremor, chorea), and diabetes mellitus. Iron in two brothers from an Italian family who presented in deposition in the basal ganglia, dentate nucleus, and panadulthood with dysphonia due to laryngeal abductor creas can be demonstrated by CT and MRI. Laboratory palsy, followed, several years later, by cerebellar ataxia studies reveal decreased or absent serum ceruloplasmin, and distal muscular atrophy and fasciculations (Barbieri decreased serum iron, and increased serum ferritin. Karak et al., 2001). Neurophysiologic studies showed a pure syndrome (MIM 608395) has been described in two sibs of motor neuropathy. The disease is slowly progressive a consanguineous Jordanian family with early-onset cereand appears to be autosomal recessive, although other bellar ataxia, dysarthria, dystonia, choreiform moveinheritance patterns could not be excluded. ments, bradykinesia, spasticity, and intellectual decline. Peripheral neuropathy, ataxia, focal necrotizing MRI showed cerebellar atrophy and iron deposition in encephalopathy, and spongy degeneration of brain the putamen (including the “eye of the tiger” sign) and (MIM 260970) is the unusual combination described substantia nigra. Linkage to the PANK2 gene was in three siblings by Appenzeller et al. (1980). The excluded (Mubaidin et al., 2003). neuropathy is probably due to an axonal defect.

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