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Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
C H A P T E R
29
Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency Florian S. Eichler Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
INTRODUCTION Disease Characteristics Sulfatides are a major component of the myelin sheath in the central and peripheral nervous system. Their accumulation leads to clinical symptoms in metachromatic leukodystrophy and multiple sulfatase deficiency. Hallmark Manifestations Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder due to arylsulfatase A deficiency.1 It encompasses three clinical subtypes: a late-infantile, a juvenile and an adult form of MLD. Age of onset within a family is usually similar. The disease is characterized by progressive neurological dysfunction and loss of previously attained milestones. MLD is usually life-limiting, with a disease course that ranges from 3 to 10 or more years in the late-infantile form and up to 20 years or more in the juvenile and adult forms. Multiple sulfatase deficiency (MSD) is due to faulty processing of an active site cysteine to formylglycine (alaninesemialdehyde), a proenzyme activation step common to most sulfatases.2 Clinical variability of multiple sulfatase deficiency is great, and features of both MLD and a mucopolysaccharidosis (MPS) may be present.3 More severe forms of MSD resemble late-infantile MLD. In milder cases, MPS-like features such as coarse facial features and skeletal abnormalities may be evident in infancy and early childhood, with MLD-like symptoms appearing in later childhood. Inheritance Both MLD and MSD are inherited in an autosomal recessive manner.2 The presence of the disease-causing mutations should be determined in both parents so that screening of at-risk relatives can occur. Carrier testing of at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in an affected family member.
Diagnosis/Testing Characteristic magnetic resonance imaging (MRI) findings in the setting of progressive neurologic symptoms should prompt testing of arylsulfatase A. MLD is suggested by arylsulfatase A (ARSA) enzyme activity in leukocytes that is less than 10% of normal controls. Approximately 0.5–2.0% of the Caucasian population shows a substantial arylsulfatase A deficiency, with a residual enzyme activity of about 10% of normal, without any clinical symptoms related to the deficiency. This phenomenon has been termed arylsulfatase A pseudodeficiency. Since the assay of ARSA enzymatic activity cannot distinguish between MLD and ARSA pseudodeficiency, molecular genetic testing of ARSA, or urinary excretion of sulfatides must confirm the diagnosis of MLD. At times, confirmation can also arise from metachromatic lipid deposits in nervous system tissue on biopsy samples.
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© 2015 Elsevier Inc. All rights reserved.
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
Features characteristic for MSD, such as facial dysmorphia, skeletal deformities, and ichthyosis, may be overlooked. Therefore, once deficiency in arylsulfatase A has been found, total arylsulfatase or another sulfatase should be assayed to prove the specificity of ARSA deficiency.
CLINICAL FEATURES Historical Overview Disease and Gene Identification The first description of a patient with MLD was published in 1910 by Alois Alzheimer. 4 Alzheimer described the metachromatic staining of the nervous system and the clinical symptoms of a patient who today would be classified as having adult onset MLD. In 1921, Witte described a patient not only with metachromatic staining in the brain but also in liver, kidney and testis. 5 In 1963, Austin et al. described the deficiency in arylsulfatase A (ARSA) in MLD; 6 2 years later, Mehl and Jatzkewitz demonstrated a block in metabolism of sulfatides. 7 The ARSA gene was mapped to the long arm of chromosome 22 band q13. 8 Austin first described MSD in 1965. 9
Mode of Inheritance and Prevalence The reported prevalence of MLD ranges from 1 : 40,000 to 1 : 160,000 in different populations.1 The disorder seems to occur throughout the world but is more prevalent in particular consanguineous populations:2 1 : 75 in Habbanite Jews in Israel, 1 : 8000 in Israeli Arabs, 1 : 10,000 in Christian Israeli Arabs, 1 : 2500 for the western portion of the Navajo Nation in the US. Since the first description of MSD in 1965, less than 100 patients have been described. Hence the true incidence and prevalence is not known.
Natural History Age of Onset, Disease Evolution and Disease Variants The three clinical subtypes of MLD differ by age of onset: late-infantile MLD, comprising 50–60% of cases; juvenile MLD, approximately 20–30%; and adult MLD, approximately 15–20%. The age of onset within a family is usually similar, but exceptions occur.10 LATE-INFANTILE MLD
The majority of patients present with motor and gait abnormalities between ages 1 and 2 years.11 One-third of the patients may present with seizures. Later signs include inability to stand, difficulty with speech, deterioration of mental function, increased muscle tone, pain in the arms and legs, generalized or partial seizures, compromised vision and hearing, and peripheral neuropathy. In the final stages children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. JUVENILE MLD
Most patients present with inattention and difficulties at school between age 4 years and sexual maturity (age 12–14 years). Gait problems, slurred speech, incontinence, and bizarre behaviors also occur. Seizures are less frequent than in the late-infantile form of the disease. Progression is similar to but slower than the late-infantile form. ADULT MLD
Symptom onset occurs in the fourth or fifth decade. Dementia and behavioral difficulties are the first symptoms.11 Patients show personality changes, alcohol or drug abuse, poor money management, and emotional lability. In others, weakness, loss of coordination, or seizures occur. Peripheral neuropathy is common. Progression is variable and may be protracted over decades. The final stage is similar to that for the earlier-onset forms.
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DIFFERENTIAL DIAGNOSIS
333
INFANTILE MSD
The classic form of MSD combines clinical features of late infantile MLD with mild features of MPS. Most children acquire the ability to stand and say a few words. During the second year, children lose acquired abilities and display staring spells, spasticity, blindness, hearing loss, swallowing difficulties, seizures and dementia. Ichthyosis develops around 2–3 years of age. Symptoms of MPS occur at variable stages of the disease and include coarse facial features, stiff joints, growth retardation, skeletal abnormalities, and hepatosplenomegaly. Age at death is usually around 10–18 years of age.
MOLECULAR GENETICS Normal Gene Product and Abnormal Gene Product(s) ARSA Enzyme Activity In MLD, the age of onset is not related to the amount of apparent enzyme activity as usually measured. Age of onset does, however, correlate reasonably well with the ability of cultured fibroblasts to degrade sulfatide added to the culture medium. In early-onset (late-infantile) MLD, affected individuals are usually homozygous or compound heterozygous for I-type ARSA-MLD alleles and make no detectable functional arylsulfatase A enzyme. Later-onset individuals with MLD have one or two A-type ARSA-MLD alleles that encode for an arylsulfatase A enzyme with some functional activity (≤ 1% when assayed with physiologic substrates).
Genotype–Phenotype Correlations A genotype–phenotype correlation for MLD has been demonstrated in several independent studies.2 It can be explained by the varying amount of residual enzyme activity associated with the genotype of the patient. Patients homozygous for alleles that do not allow for the expression of any enzyme activity (i.e., null alleles) always suffer from the most severe late-infantile form of the disease. The most frequent allele is the IVS459 + 1A > G splice donor site mutation of exon 2. Most mutations in late-infantile patients, however, are missense mutations. This causes misfolding and trapping of the enzyme in the endoplasmic reticulum, so that no functional enzyme reaches the lysosome. Many cases of juvenile-onset MLD are associated with heterozygosity for a null allele and a non-null allele.2 Occasionally this is also found in adult-onset patients. More commonly, though, adult-onset disease shows expression of low amounts of enzyme activity, secondary to alleles being missense mutations. The residual enzyme in these cases can degrade small amounts of sulfatide.
DISEASE MECHANISMS Pathophysiology MLD and MSD are disorders of impaired breakdown of sulfatides (cerebroside sulfate or 3-O-sulfogalactosylceramide), sulfate-containing lipids that occur throughout the body and are found in greatest abundance in nervous tissue, kidneys, and testes. Sulfatides are critical constituents of the nervous system, where they comprise approximately 5% of myelin lipids. Nervous system sulfatide accumulation is not restricted to glial cells, however, but also occurs in neurons. Sulfatide accumulation in the nervous system eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder.1
DIFFERENTIAL DIAGNOSIS Other Leukodystrophies and Lysosomal Storage Diseases Clinically, MLD is often difficult to differentiate from other progressive degenerative disorders that manifest after initial normal development (Table 29.1). Delayed development in late infancy most often leads to MRI evaluation that can reveal a characteristic pattern of injury. If symmetric confluent white matter changes are present on MRI,
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
TABLE 29.1 Differential Diagnosis of MLD and MSD Disorder
Clinical manifestations
Urinary excretion
Enzyme activity
MLD
See above
Elevated sulfatide
Low ARSA enzyme activity
MSD
MLD-like clinical picture, with elevated CSF protein and slowed nerve conduction velocity; MPS-like features, and ichthyosis
Elevated sulfatide and mucopolysaccharides
Very low ARSA enzyme activity; deficiency of most sulfatases in leukocytes or cultured cells
Saposin B deficiency
Similar to MLD
Elevated sulfatide and other glycolipids
ARSA enzyme activity within normal range
Other leukodystrophies
Progressive motor and cognitive decline with variable age of onset
Normal sulfatide and other glycolipids
ARSA enzyme activity within normal range
Adapted from Fluharty AL. Arylsulfatase A Deficiency, Gene Reviews; 2014. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1130/, Accessed May 2014.
other conditions to consider are Krabbe disease and X-linked adrenoleukodystrophy. Hypomyelinating disorders such as Pelizaeus–Merzbacher disease lack the sparing of the subcortical white matter usually seen in metachromatic leukodystrophy. Although some mucopolysaccharidoses can have a similar presentation to MLD, the most characteristic physical features seen in most mucopolysaccharidoses are not found in individuals with MLD but can be seen in some patients with MSD. The evaluation of appropriate lysosomal enzymes can distinguish these disorders. It should be kept in mind that low ARSA enzyme activity caused by arylsulfatase pseudodeficiency can be found in association with many disorders. As mentioned above, further genetic and/or urinary sulfatide testing is needed to confirm whether the biochemical changes are disease-causing or not.
TESTING Neuroimaging MLD has a characteristic pattern that is quite similar among the late-infantile, juvenile- and adult-onset form of the disease12 (Figure 29.1). A diffuse sheet-like area of increased T2 signal hyperintensity first involves the frontal and parietal periventricular and central white matter regions. In early disease this can be quite faint and mistakenly thought to be terminal zones of myelination. As severe disease develops the sheet of white matter signal intensity involves the inner half of the subcortical white matter. A tigroid pattern emerges.
MANAGEMENT Standard of Care The burden of disease upon both patient and caregiver should not be underestimated. Close collaboration with nursing care helps address the many changing needs of the patient. Supportive therapies to reduce pain and spasticity and optimize hygiene help avoid many end-stage care problems. The 5-year survival has improved since 1970 due to much improved supportive care. Provision of an enriched environment and an intense but appropriately cautious physical therapy program provides an optimized quality of life at all stages of the disease. The timely use of suction equipment, swallowing aids, feeding tubes, and other supportive measures can improve quality life. Seizures and contractures should be treated with antiepileptic drugs and muscle relaxants, respectively. Gastroesophageal reflux, constipation, and drooling are common problems that may be helped by specific medications. Many practitioners are not aware of the increased risk of gall bladder stones in MLD. This can be a significant source of pain in a nonverbal child, and detecting and treating this may help relieve pain and discomfort.
Prevention of Primary Manifestations Hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) has long been employed to treat the primary central nervous system manifestations of MLD.13 Transplantations for leukodystrophies occur worldwide.14 However, not all individuals with MLD are suitable candidates for these procedures. Overall, children III. NEUROMETABOLIC DISORDERS
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Management
A
B
D
C
E
FIGURE 29.1 MRI of late-infantile metachromatic leukodystrophy in a male child. The child was born prematurely at 34 weeks gestation due to preeclampsia. At 2 weeks of life, ultrasound (not shown) had illustrated hyperechoic foci in the bilateral posterior parietal periventricular white matter. (A, B) Age 21 months: Bilateral increased T2-signal abnormality involving the centrum semiovale, corona radiata, periventricular and deep white matter of cerebral hemispheres with relative sparing of the subcortical U fibers. There are multiple foci of signal dropout within the left centrum semiovale and bilateral periventricular white matter, representing foci of remote hemorrhage or calcification. (C, D) Age 30 months: Dilation of the lateral ventricles and prominence of the sulci have become prominent. As before, there is increased T2 signal in the centrum semiovale and corona radiata white matter. (E) Susceptibility-weighted imaging at 30 months of age illustrates scattered hemorrhagic foci with possible mineralization in the centrum semiovale, corona radiata, thalami and globus pallidus. Figure courtesy of Dr. Juan M. Pascual, UT Southwestern Medical Center, with permission.
with juvenile-onset MLD have better outcomes than those with late-infantile MLD.15 Substantial risk is involved and long-term effects are unclear. Patients with motor function symptoms at the time of transplant do not improve after transplantation.16 Brainstem auditory-evoked responses, visual-evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilize or improve in juvenile patients but continue to worsen in most patients with the late infantile presentation. Pretransplant modified Loes scores are highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who are asymptomatic at the time of transplantation benefit most from the procedure. Children with juvenile onset and minimal symptoms show stabilization or deterioration of motor skills but maintained cognitive skills.
Therapies Under Investigation Enzyme Replacement Therapy (ERT) Clinical testing of intravenous recombinant human enzyme was halted after a phase I/II study failed to show substantial improvement. As the major obstacle to ERT has been bypassing the blood–brain barrier, other routes of delivery, such as intrathecal administration, are being pursued. In addition, different forms of human ARSA enzyme III. NEUROMETABOLIC DISORDERS
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
are now available, and animal studies suggest that it may be a useful supplement to other therapies.16 Questions have been raised that the enzymes used in various clinical trials may have had different uptake properties.17 Gene Therapy In the past 10 years much progress has been made in the field of gene therapies for arylsulfatase A. First results of a human gene replacement trial have recently been reported. In three presymptomatic patients, treatment with autologous CD34 cells that had undergone lentiviral gene correction appeared to be safe and effective over a 2-year follow-up period. Some concerns have been raised about the long-term safety of this approach, but the results are encouraging.18 Trials are also underway for AAVrh.10 gene delivery in MLD. Different from the lentiviral gene correction mentioned above this is undertaken by direct intracerebral injection.19 While this necessitates surgery, it may allow for a more rapid delivery in this progressive condition. Colle et al.20 injected an adeno-associated virus vector containing human ARSA into the brains of nonhuman primates and found that the enzyme was expressed without adverse effects, supporting that a similar approach may be feasible and safe in humans.
References 1. von-Figura KGV, Jaeken J. Metachromatic leukodystrophy. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3695–3724. 2. Fluharty AL. Arylsulfatase A Deficiency, Gene Reviews; 2014. http://www.ncbi.nlm.nih.gov/books/NBK1130/, Accessed May 2014. 3. Macaulay RJ, Lowry NJ, Casey RE. Pathologic findings of multiple sulfatase deficiency reflect the pattern of enzyme deficiencies. Pediatr Neurol. 1998;19:372–376. 4. Alzheimer A: Beitraege zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgaengen im Nerven gewebe. Nissl-Alzheimer’s Histol Histopathol Arb 3: 1910;401. 5. Witte F. Ueber pathologische Abbauvorgange im Zentralnervensystem. Munch Med Wochenschr. 1921;68:69. 6. Austin J. Recent studies in the metachromatic and globoid body forms of diffuse sclerosis. In: Folch-Pi JAB H, ed. Brain Lipids and Lipoproteins and Leucodystrophies. 1st ed. New York: Elsevier Publishing Company; 1963. 7. Mehl E, Jatzkewitz H. Evidence for the genetic block in metachromatic leucodystrophy (Ml). Biochem Biophys Res Commun. 1965;19:407–411. 8. Phelan MC1, Thomas GR, Saul RA, et al. Cytogenetic, biochemical, and molecular analyses of a 22q13 deletion. Am J Med Genet. 1992;43(5):872–876. 9. Austin JH, Balasubramanian AS, Pattabiraman TN, et al. A Controlled Study of Enzymic Activities in three Human Disorders of Glycolipid Metabolism. J Neurochem. 1963;10:805–816. 10. Arbour LT, Silver K, Hechtman P, et al. Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol. 2000;23(2):173–176. 11. Mahmood A, Berry J, Wenger D, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol. 2010;25(5):572–580. 12. Eichler F, Grodd W, Grant E, et al. Metachromatic leukodystrophy: a scoring system for brain MR observations. AJNR Am J Neuroradiol. 2009;30(10):1893–1897. 13. Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol. 1999;12:167–176. 14. Musolino PL, Lund TC, Pan J, et al. Hematopoietic stem cell transplantation in the leukodystrophies: a systematic review of the literature. Neuropediatrics. 2014;45(3):169–174. 15. Martin HR, Poe MD, Provenzale JM, et al. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol Blood Marrow Transplant. 2013;19(4):616–624. 16. Matzner U, Herbst E, Hedayati KK, et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. 2005;14:1139–1152. 17. Schröder S, Matthes F, Hyden P, et al. Site-specific analysis of N-linked oligosaccharides of recombinant lysosomal arylsulfatase A produced in different cell lines. Glycobiology. 2010 Feb;20(2):248–259. 18. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. 19. Piguet F, Sondhi D, Piraud M, et al. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther. 2012;23(8):903–914. 20. Colle MA, Piguet F, Bertrand L, et al. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet. 2010;19(1):147–158.
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Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency Florian S. Eichler Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
INTRODUCTION Disease Characteristics Sulfatides are a major component of the myelin sheath in the central and peripheral nervous system. Their accumulation leads to clinical symptoms in metachromatic leukodystrophy and multiple sulfatase deficiency. Hallmark Manifestations Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder due to arylsulfatase A deficiency.1 It encompasses three clinical subtypes: a late-infantile, a juvenile and an adult form of MLD. Age of onset within a family is usually similar. The disease is characterized by progressive neurological dysfunction and loss of previously attained milestones. MLD is usually life-limiting, with a disease course that ranges from 3 to 10 or more years in the late-infantile form and up to 20 years or more in the juvenile and adult forms. Multiple sulfatase deficiency (MSD) is due to faulty processing of an active site cysteine to formylglycine (alaninesemialdehyde), a proenzyme activation step common to most sulfatases.2 Clinical variability of multiple sulfatase deficiency is great, and features of both MLD and a mucopolysaccharidosis (MPS) may be present.3 More severe forms of MSD resemble late-infantile MLD. In milder cases, MPS-like features such as coarse facial features and skeletal abnormalities may be evident in infancy and early childhood, with MLD-like symptoms appearing in later childhood. Inheritance Both MLD and MSD are inherited in an autosomal recessive manner.2 The presence of the disease-causing mutations should be determined in both parents so that screening of at-risk relatives can occur. Carrier testing of at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in an affected family member.
Diagnosis/Testing Characteristic magnetic resonance imaging (MRI) findings in the setting of progressive neurologic symptoms should prompt testing of arylsulfatase A. MLD is suggested by arylsulfatase A (ARSA) enzyme activity in leukocytes that is less than 10% of normal controls. Approximately 0.5–2.0% of the Caucasian population shows a substantial arylsulfatase A deficiency, with a residual enzyme activity of about 10% of normal, without any clinical symptoms related to the deficiency. This phenomenon has been termed arylsulfatase A pseudodeficiency. Since the assay of ARSA enzymatic activity cannot distinguish between MLD and ARSA pseudodeficiency, molecular genetic testing of ARSA, or urinary excretion of sulfatides must confirm the diagnosis of MLD. At times, confirmation can also arise from metachromatic lipid deposits in nervous system tissue on biopsy samples.
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
Features characteristic for MSD, such as facial dysmorphia, skeletal deformities, and ichthyosis, may be overlooked. Therefore, once deficiency in arylsulfatase A has been found, total arylsulfatase or another sulfatase should be assayed to prove the specificity of ARSA deficiency.
CLINICAL FEATURES Historical Overview Disease and Gene Identification The first description of a patient with MLD was published in 1910 by Alois Alzheimer. 4 Alzheimer described the metachromatic staining of the nervous system and the clinical symptoms of a patient who today would be classified as having adult onset MLD. In 1921, Witte described a patient not only with metachromatic staining in the brain but also in liver, kidney and testis. 5 In 1963, Austin et al. described the deficiency in arylsulfatase A (ARSA) in MLD; 6 2 years later, Mehl and Jatzkewitz demonstrated a block in metabolism of sulfatides. 7 The ARSA gene was mapped to the long arm of chromosome 22 band q13. 8 Austin first described MSD in 1965. 9
Mode of Inheritance and Prevalence The reported prevalence of MLD ranges from 1 : 40,000 to 1 : 160,000 in different populations.1 The disorder seems to occur throughout the world but is more prevalent in particular consanguineous populations:2 1 : 75 in Habbanite Jews in Israel, 1 : 8000 in Israeli Arabs, 1 : 10,000 in Christian Israeli Arabs, 1 : 2500 for the western portion of the Navajo Nation in the US. Since the first description of MSD in 1965, less than 100 patients have been described. Hence the true incidence and prevalence is not known.
Natural History Age of Onset, Disease Evolution and Disease Variants The three clinical subtypes of MLD differ by age of onset: late-infantile MLD, comprising 50–60% of cases; juvenile MLD, approximately 20–30%; and adult MLD, approximately 15–20%. The age of onset within a family is usually similar, but exceptions occur.10 LATE-INFANTILE MLD
The majority of patients present with motor and gait abnormalities between ages 1 and 2 years.11 One-third of the patients may present with seizures. Later signs include inability to stand, difficulty with speech, deterioration of mental function, increased muscle tone, pain in the arms and legs, generalized or partial seizures, compromised vision and hearing, and peripheral neuropathy. In the final stages children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. JUVENILE MLD
Most patients present with inattention and difficulties at school between age 4 years and sexual maturity (age 12–14 years). Gait problems, slurred speech, incontinence, and bizarre behaviors also occur. Seizures are less frequent than in the late-infantile form of the disease. Progression is similar to but slower than the late-infantile form. ADULT MLD
Symptom onset occurs in the fourth or fifth decade. Dementia and behavioral difficulties are the first symptoms.11 Patients show personality changes, alcohol or drug abuse, poor money management, and emotional lability. In others, weakness, loss of coordination, or seizures occur. Peripheral neuropathy is common. Progression is variable and may be protracted over decades. The final stage is similar to that for the earlier-onset forms.
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DIFFERENTIAL DIAGNOSIS
333
INFANTILE MSD
The classic form of MSD combines clinical features of late infantile MLD with mild features of MPS. Most children acquire the ability to stand and say a few words. During the second year, children lose acquired abilities and display staring spells, spasticity, blindness, hearing loss, swallowing difficulties, seizures and dementia. Ichthyosis develops around 2–3 years of age. Symptoms of MPS occur at variable stages of the disease and include coarse facial features, stiff joints, growth retardation, skeletal abnormalities, and hepatosplenomegaly. Age at death is usually around 10–18 years of age.
MOLECULAR GENETICS Normal Gene Product and Abnormal Gene Product(s) ARSA Enzyme Activity In MLD, the age of onset is not related to the amount of apparent enzyme activity as usually measured. Age of onset does, however, correlate reasonably well with the ability of cultured fibroblasts to degrade sulfatide added to the culture medium. In early-onset (late-infantile) MLD, affected individuals are usually homozygous or compound heterozygous for I-type ARSA-MLD alleles and make no detectable functional arylsulfatase A enzyme. Later-onset individuals with MLD have one or two A-type ARSA-MLD alleles that encode for an arylsulfatase A enzyme with some functional activity (≤ 1% when assayed with physiologic substrates).
Genotype–Phenotype Correlations A genotype–phenotype correlation for MLD has been demonstrated in several independent studies.2 It can be explained by the varying amount of residual enzyme activity associated with the genotype of the patient. Patients homozygous for alleles that do not allow for the expression of any enzyme activity (i.e., null alleles) always suffer from the most severe late-infantile form of the disease. The most frequent allele is the IVS459 + 1A > G splice donor site mutation of exon 2. Most mutations in late-infantile patients, however, are missense mutations. This causes misfolding and trapping of the enzyme in the endoplasmic reticulum, so that no functional enzyme reaches the lysosome. Many cases of juvenile-onset MLD are associated with heterozygosity for a null allele and a non-null allele.2 Occasionally this is also found in adult-onset patients. More commonly, though, adult-onset disease shows expression of low amounts of enzyme activity, secondary to alleles being missense mutations. The residual enzyme in these cases can degrade small amounts of sulfatide.
DISEASE MECHANISMS Pathophysiology MLD and MSD are disorders of impaired breakdown of sulfatides (cerebroside sulfate or 3-O-sulfogalactosylceramide), sulfate-containing lipids that occur throughout the body and are found in greatest abundance in nervous tissue, kidneys, and testes. Sulfatides are critical constituents of the nervous system, where they comprise approximately 5% of myelin lipids. Nervous system sulfatide accumulation is not restricted to glial cells, however, but also occurs in neurons. Sulfatide accumulation in the nervous system eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder.1
DIFFERENTIAL DIAGNOSIS Other Leukodystrophies and Lysosomal Storage Diseases Clinically, MLD is often difficult to differentiate from other progressive degenerative disorders that manifest after initial normal development (Table 29.1). Delayed development in late infancy most often leads to MRI evaluation that can reveal a characteristic pattern of injury. If symmetric confluent white matter changes are present on MRI,
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
TABLE 29.1 Differential Diagnosis of MLD and MSD Disorder
Clinical manifestations
Urinary excretion
Enzyme activity
MLD
See above
Elevated sulfatide
Low ARSA enzyme activity
MSD
MLD-like clinical picture, with elevated CSF protein and slowed nerve conduction velocity; MPS-like features, and ichthyosis
Elevated sulfatide and mucopolysaccharides
Very low ARSA enzyme activity; deficiency of most sulfatases in leukocytes or cultured cells
Saposin B deficiency
Similar to MLD
Elevated sulfatide and other glycolipids
ARSA enzyme activity within normal range
Other leukodystrophies
Progressive motor and cognitive decline with variable age of onset
Normal sulfatide and other glycolipids
ARSA enzyme activity within normal range
Adapted from Fluharty AL. Arylsulfatase A Deficiency, Gene Reviews; 2014. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1130/, Accessed May 2014.
other conditions to consider are Krabbe disease and X-linked adrenoleukodystrophy. Hypomyelinating disorders such as Pelizaeus–Merzbacher disease lack the sparing of the subcortical white matter usually seen in metachromatic leukodystrophy. Although some mucopolysaccharidoses can have a similar presentation to MLD, the most characteristic physical features seen in most mucopolysaccharidoses are not found in individuals with MLD but can be seen in some patients with MSD. The evaluation of appropriate lysosomal enzymes can distinguish these disorders. It should be kept in mind that low ARSA enzyme activity caused by arylsulfatase pseudodeficiency can be found in association with many disorders. As mentioned above, further genetic and/or urinary sulfatide testing is needed to confirm whether the biochemical changes are disease-causing or not.
TESTING Neuroimaging MLD has a characteristic pattern that is quite similar among the late-infantile, juvenile- and adult-onset form of the disease12 (Figure 29.1). A diffuse sheet-like area of increased T2 signal hyperintensity first involves the frontal and parietal periventricular and central white matter regions. In early disease this can be quite faint and mistakenly thought to be terminal zones of myelination. As severe disease develops the sheet of white matter signal intensity involves the inner half of the subcortical white matter. A tigroid pattern emerges.
MANAGEMENT Standard of Care The burden of disease upon both patient and caregiver should not be underestimated. Close collaboration with nursing care helps address the many changing needs of the patient. Supportive therapies to reduce pain and spasticity and optimize hygiene help avoid many end-stage care problems. The 5-year survival has improved since 1970 due to much improved supportive care. Provision of an enriched environment and an intense but appropriately cautious physical therapy program provides an optimized quality of life at all stages of the disease. The timely use of suction equipment, swallowing aids, feeding tubes, and other supportive measures can improve quality life. Seizures and contractures should be treated with antiepileptic drugs and muscle relaxants, respectively. Gastroesophageal reflux, constipation, and drooling are common problems that may be helped by specific medications. Many practitioners are not aware of the increased risk of gall bladder stones in MLD. This can be a significant source of pain in a nonverbal child, and detecting and treating this may help relieve pain and discomfort.
Prevention of Primary Manifestations Hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) has long been employed to treat the primary central nervous system manifestations of MLD.13 Transplantations for leukodystrophies occur worldwide.14 However, not all individuals with MLD are suitable candidates for these procedures. Overall, children III. NEUROMETABOLIC DISORDERS
335
Management
A
B
D
C
E
FIGURE 29.1 MRI of late-infantile metachromatic leukodystrophy in a male child. The child was born prematurely at 34 weeks gestation due to preeclampsia. At 2 weeks of life, ultrasound (not shown) had illustrated hyperechoic foci in the bilateral posterior parietal periventricular white matter. (A, B) Age 21 months: Bilateral increased T2-signal abnormality involving the centrum semiovale, corona radiata, periventricular and deep white matter of cerebral hemispheres with relative sparing of the subcortical U fibers. There are multiple foci of signal dropout within the left centrum semiovale and bilateral periventricular white matter, representing foci of remote hemorrhage or calcification. (C, D) Age 30 months: Dilation of the lateral ventricles and prominence of the sulci have become prominent. As before, there is increased T2 signal in the centrum semiovale and corona radiata white matter. (E) Susceptibility-weighted imaging at 30 months of age illustrates scattered hemorrhagic foci with possible mineralization in the centrum semiovale, corona radiata, thalami and globus pallidus. Figure courtesy of Dr. Juan M. Pascual, UT Southwestern Medical Center, with permission.
with juvenile-onset MLD have better outcomes than those with late-infantile MLD.15 Substantial risk is involved and long-term effects are unclear. Patients with motor function symptoms at the time of transplant do not improve after transplantation.16 Brainstem auditory-evoked responses, visual-evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilize or improve in juvenile patients but continue to worsen in most patients with the late infantile presentation. Pretransplant modified Loes scores are highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who are asymptomatic at the time of transplantation benefit most from the procedure. Children with juvenile onset and minimal symptoms show stabilization or deterioration of motor skills but maintained cognitive skills.
Therapies Under Investigation Enzyme Replacement Therapy (ERT) Clinical testing of intravenous recombinant human enzyme was halted after a phase I/II study failed to show substantial improvement. As the major obstacle to ERT has been bypassing the blood–brain barrier, other routes of delivery, such as intrathecal administration, are being pursued. In addition, different forms of human ARSA enzyme III. NEUROMETABOLIC DISORDERS
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29. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency
are now available, and animal studies suggest that it may be a useful supplement to other therapies.16 Questions have been raised that the enzymes used in various clinical trials may have had different uptake properties.17 Gene Therapy In the past 10 years much progress has been made in the field of gene therapies for arylsulfatase A. First results of a human gene replacement trial have recently been reported. In three presymptomatic patients, treatment with autologous CD34 cells that had undergone lentiviral gene correction appeared to be safe and effective over a 2-year follow-up period. Some concerns have been raised about the long-term safety of this approach, but the results are encouraging.18 Trials are also underway for AAVrh.10 gene delivery in MLD. Different from the lentiviral gene correction mentioned above this is undertaken by direct intracerebral injection.19 While this necessitates surgery, it may allow for a more rapid delivery in this progressive condition. Colle et al.20 injected an adeno-associated virus vector containing human ARSA into the brains of nonhuman primates and found that the enzyme was expressed without adverse effects, supporting that a similar approach may be feasible and safe in humans.
References 1. von-Figura KGV, Jaeken J. Metachromatic leukodystrophy. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3695–3724. 2. Fluharty AL. Arylsulfatase A Deficiency, Gene Reviews; 2014. http://www.ncbi.nlm.nih.gov/books/NBK1130/, Accessed May 2014. 3. Macaulay RJ, Lowry NJ, Casey RE. Pathologic findings of multiple sulfatase deficiency reflect the pattern of enzyme deficiencies. Pediatr Neurol. 1998;19:372–376. 4. Alzheimer A: Beitraege zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgaengen im Nerven gewebe. Nissl-Alzheimer’s Histol Histopathol Arb 3: 1910;401. 5. Witte F. Ueber pathologische Abbauvorgange im Zentralnervensystem. Munch Med Wochenschr. 1921;68:69. 6. Austin J. Recent studies in the metachromatic and globoid body forms of diffuse sclerosis. In: Folch-Pi JAB H, ed. Brain Lipids and Lipoproteins and Leucodystrophies. 1st ed. New York: Elsevier Publishing Company; 1963. 7. Mehl E, Jatzkewitz H. Evidence for the genetic block in metachromatic leucodystrophy (Ml). Biochem Biophys Res Commun. 1965;19:407–411. 8. Phelan MC1, Thomas GR, Saul RA, et al. Cytogenetic, biochemical, and molecular analyses of a 22q13 deletion. Am J Med Genet. 1992;43(5):872–876. 9. Austin JH, Balasubramanian AS, Pattabiraman TN, et al. A Controlled Study of Enzymic Activities in three Human Disorders of Glycolipid Metabolism. J Neurochem. 1963;10:805–816. 10. Arbour LT, Silver K, Hechtman P, et al. Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol. 2000;23(2):173–176. 11. Mahmood A, Berry J, Wenger D, et al. Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol. 2010;25(5):572–580. 12. Eichler F, Grodd W, Grant E, et al. Metachromatic leukodystrophy: a scoring system for brain MR observations. AJNR Am J Neuroradiol. 2009;30(10):1893–1897. 13. Krivit W, Peters C, Shapiro EG. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr Opin Neurol. 1999;12:167–176. 14. Musolino PL, Lund TC, Pan J, et al. Hematopoietic stem cell transplantation in the leukodystrophies: a systematic review of the literature. Neuropediatrics. 2014;45(3):169–174. 15. Martin HR, Poe MD, Provenzale JM, et al. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol Blood Marrow Transplant. 2013;19(4):616–624. 16. Matzner U, Herbst E, Hedayati KK, et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. 2005;14:1139–1152. 17. Schröder S, Matthes F, Hyden P, et al. Site-specific analysis of N-linked oligosaccharides of recombinant lysosomal arylsulfatase A produced in different cell lines. Glycobiology. 2010 Feb;20(2):248–259. 18. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. 19. Piguet F, Sondhi D, Piraud M, et al. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther. 2012;23(8):903–914. 20. Colle MA, Piguet F, Bertrand L, et al. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet. 2010;19(1):147–158.
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