Hereditary Ataxias

Abstract

There are many causes of hereditary ataxia. These can be grouped into categories of autosomal recessive, autosomal dominant, and X-linked. Molecularly, many of them are due to trinucleotide repeat expansions. In Friedreich ataxia, the trinucleotide repeat expansions lead to a “loss of function.” In the dominant ataxias, the expanded repeats lead to a “gain of function,” most likely through accumulation of intranuclear (and less commonly cytoplasmic) polyglutamine inclusions. Channelopathies can also lead to ataxia, especially episodic ataxia. Although phenotypic characteristics are an aid to the clinician, a definitive diagnosis is usually made only through genotypic or molecular studies. Genetic counseling is necessary for the testing of symptomatic and asymptomatic individuals. No effective treatment is yet available for most ataxic syndromes, except for ataxia with isolated vitamin E deficiency and the episodic ataxias. There are many causes of hereditary ataxia. These can be grouped into categories of autosomal recessive, autosomal dominant, and X-linked. Molecularly, many of them are due to trinucleotide repeat expansions. In Friedreich ataxia, the trinucleotide repeat expansions lead to a “loss of function.” In the dominant ataxias, the expanded repeats lead to a “gain of function,” most likely through accumulation of intranuclear (and less commonly cytoplasmic) polyglutamine inclusions. Channelopathies can also lead to ataxia, especially episodic ataxia. Although phenotypic characteristics are an aid to the clinician, a definitive diagnosis is usually made only through genotypic or molecular studies. Genetic counseling is necessary for the testing of symptomatic and asymptomatic individuals. No effective treatment is yet available for most ataxic syndromes, except for ataxia with isolated vitamin E deficiency and the episodic ataxias. The hereditary spinocerebellar ataxias (SeAs) include autosomal recessive, autosomal dominant, and Xlinked inherited diseases, all of which have overlapping phenotypes. Clinical classification is difficult because of the phenotypic overlap. With the evolution of molecular genetics, the loci and mutations for many of the ataxias have been identified, allowing more definitive molecular classification. Advances in imaging have led to a clearer premortem definition of structural changes, giving insight into pre symptomatic features and natural history and pro-· viding tools for gauging interventions. Transgenic models have enhanced our understanding of these disorders, and they may facilitate the formulation of interventional treatment strategies. Diseases with common underlying molecular mechanisms may respond to similar treatments. We review the nonmetabolic hereditary ataxias according to their mode of inheritance and list the phenotypic and genotypic characteristics for each disorder to aid the clinician in the evaluation of hereditary ataxias. “Loss of function” leads to the abnormalities of Friedreich ataxia (FA), which is due to a triplet repeat GAA expansion and subsequent decreased transcription of the protein frataxin.1Campuzano V Montermini L Molto MD et al.Friedrcich's ataxia: autosomal recessive disease caused by an imronic GAA triplei repeal expansion.Science. 1996; 271: 1423-1427Crossref PubMed Google Scholar, 2Bidichandani SI Ashizawa T Patel PI The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.Am J Hum Genet. 1998; 62: 111-121Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar By comparison, several autosomal dominant cerebellar ataxias (ADCAs) result from CAG repeat expansions, which are believed to result in a “gain of function.” The proteins encoded by these polyglutamine stretches are often ubiquitously expressed in the central nervous system, and the mechanism by which they lead to selective cerebellar neuronal dysfunction and death remains to be determined. Three of the ADCAs are known to be ion channel disorders: SCA type 6 and episodic ataxia type 1 (EA-l) and type 2 (EA-2). Friedreich ataxia is the most common cause of hereditary ataxia, with an estimated incidence of 1 in 20,000 and a prevalence of 1 in 50,000 persons.3Durr A Cossee M Agid Y et al.Clinical and genetic abnormalities in patients with Friedreich's ataxia.N Engl J Med. 1996; 335: 1169-1175Crossref PubMed Scopus (476) Google Scholar, 4Geoffroy G Barbeau A Breton G et al.Clinical description and rocntgcnologic evaluation of patients with Friedreich's ataxia.Can J Neural Sci. 1976; 3: 279-286PubMed Google Scholar The cardinal features include gait and limb ataxia, dysarthria, absent muscle stretch reflexes in the lower limbs, sensory loss, and signs of corticospinal tract disease. Skeletal abnormalities, cardiomyopathy, and impaired glucose tolerance or diabetes are often encountered. The onset is usually before a patient is 20 years old, and progression is relentless. Because FA is common, the diagnosis is often based on the triad of progressive cerebellar dysfunction, hypoactive knee and ankle jerks, and preadolescent onset.3Durr A Cossee M Agid Y et al.Clinical and genetic abnormalities in patients with Friedreich's ataxia.N Engl J Med. 1996; 335: 1169-1175Crossref PubMed Scopus (476) Google Scholar, 4Geoffroy G Barbeau A Breton G et al.Clinical description and rocntgcnologic evaluation of patients with Friedreich's ataxia.Can J Neural Sci. 1976; 3: 279-286PubMed Google Scholar, 5Filla A Cavalcanti F De Michèle G et al.Friedreich's ataxia after gene cloning: the sensitivity and specificity of clinical diagnosis [abstract].Neurology. 1997; 48: A178-A179Google Scholar Nerve conduction studies commonly show a sensory axonal neuropathy. The major pathologic changes in FA include severe demyelination in the dorsal columns (especially the fasciculus gracilis) and, to a lesser degree, the lateral columns, dorsal spinocerebellar tracts, posterior roots, and peripheral nerves. Positron emission tomography with use of fluorodeoxyglucose F 12 revealsa widespread increase in the cerebral metabolic rate for glucose early in the course of disease.6Gilman S Junck L Markel DS Koeppe RA Kluin KJ Cerebral glucose hypermclabolism in Friedreich's ataxia detected with positron emission tomography.Ann Neurol. 1990; 28: 750-757Crossref PubMed Scopus (25) Google Scholar As the disease progresses, the hypermetabolism declines substantially in correlation with an increase in clinical severity and cerebral atrophy.7Junck L Gilman S Gebarski SS Koeppe RA Kluin KJ Markel DS Structural and functional brain imaging in Friedreich's ataxia.Arch Neurol. 1994; 51: 349-355Crossref PubMed Google Scholar Friedreich ataxia is due to a genetic defect in the frataxin gene, which maps to chromosome 9q13.1Campuzano V Montermini L Molto MD et al.Friedrcich's ataxia: autosomal recessive disease caused by an imronic GAA triplei repeal expansion.Science. 1996; 271: 1423-1427Crossref PubMed Google Scholar Although 6% of patients with FA have point mutations in the frataxin gene, 94% have an unstable GAA trinucleotide expansion in the first intron of this gene (Table 1); 75% to of those with allele expansions are homozygotes. Affected individuals have GAA repeat expansion sizes ranging from 66 to 1700, whereas chromosomes in healthy persons contain 7 to 28 GAA repeats.1Campuzano V Montermini L Molto MD et al.Friedrcich's ataxia: autosomal recessive disease caused by an imronic GAA triplei repeal expansion.Science. 1996; 271: 1423-1427Crossref PubMed Google Scholar, 2Bidichandani SI Ashizawa T Patel PI The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.Am J Hum Genet. 1998; 62: 111-121Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 5Filla A Cavalcanti F De Michèle G et al.Friedreich's ataxia after gene cloning: the sensitivity and specificity of clinical diagnosis [abstract].Neurology. 1997; 48: A178-A179Google Scholar, 8Epplen C Epplen JT Frank G Milerski B Santos KJ Schols L Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene.Hum Genet. 1997; 99: 834-836Crossref PubMed Scopus (91) Google Scholar Larger GAA expansions are associated with onset at a younger age and more severe phenotypes, including diabetes and cardiomyopathy.Table 1Genotypic Characteristics of the Autosomal Recessive Spinocerebellar Ataxias*α-TTP = α-tocopherol transfer protein; CS = Cockayne syndrome; CSTB = cystatin B; NF = neurofilament; XP= xeroderma pigmentosum.Type of ataxiaChromasomeGene mutationGene productDNA testingFricdrcich ataxia9q13About 6% have point mutations in the frataxin gene, whereas 94% have GAA repeat expansions in the frataxin gene (at least 75% are homozygotcsj†Chromosomcs in healthy persons have 7 to 28 GAA repeats, whereas those in persons with Friedreich ataxia have 66 to 1700 GAA repeats.Mutations of frataxin gene theorized to affect mitochondrial DNA repair or replicationCommercially availableAtaxia with isolated vitamin E deficiency8q1368% with frameshil't 744delA mutation in the TTP1 gene; point mutation at position 101 of the TTP gene (histidine replaced withglutamine)Ct-TTP protein, incorporates α-tocophcrol into lipoproteins in the liverCommerically availableEarly-onset cerebellar ataxia with retained reflexesLikely heterogeneousUnknownUnknownNonePosterior column ataxia with retinitis pigmentosaUnknownUnknownUnknownNoneInfantile onset spinocerebellar ataxia10q23.3-24.1Possibly in NF-66NF-66Linkage analysisMyoclonus-ataxia syndromes Ramsay Hunt syndromeUnknownUnknownUnknownNone Unverricht-Lundborg disease21q22,3CSTB gene, most have 12- to 18-mer mini-satellite repeat expansion in CSTB gene; some with insertions, deletions, missense mutations in CSTB geneCSTB. a cysteine protease inhibitorPossibleAtaxia with hypogonadismUnknownUnknownUnknownNoneMarinesco-Sjogrcn syndromeUnknownUnknownUnknownNoneBehr syndromeUnknownUnknownUnknownNoneAtaxia with deafnessUnknownUnknownUnknownNoneAtaxia-tclangicctasiaI lq22-23Nonsense, missense mutations and insertions in ATM geneATM prolein involved in ensuring the fidelity of DNA repair and cell cycle regulation after genome damagePossibleI4qll, 7pt3-15, 7q32-35Chromosomal translationsXPPossible XPA9q34.1XPA geneXPA XPB2q21XPBIERCC3 geneXPB XPC3p25.1XPC geneXPC XP-D19±3.2XPDIERCC2 geneXPD XP-EUnknownUnknownXPE XP-F16p13ERCC4 geneXPl XPG13q32-33ERCC5 geneXPGCSPossible CSA5CSA or CKNI geneCSA CSB10q21.lCSB or ERCCf) geneCSB CS/XP-B10ERCC6 geneXPB CS/XP-D19q13.2ERCC2 geneXPD CS/XP-C13ERCC5 geneXPG* α-TTP = α-tocopherol transfer protein; CS = Cockayne syndrome; CSTB = cystatin B; NF = neurofilament; XP= xeroderma pigmentosum.† Chromosomcs in healthy persons have 7 to 28 GAA repeats, whereas those in persons with Friedreich ataxia have 66 to 1700 GAA repeats. Open table in a new tab The phenotype of FA has been broadened to include the following: late-onset FA (in patients older than 20–25 years), which has a benign course and a lower incidence of skeletal deformities; families in which affected individuals have the FA phenotype except for retained reflexes (FARR); and the Acadian (Louisiana) form, with slower peripheral progression, lower incidence of cardiomyopathy, and longer life span.9De Michele G Fitla A Cavalcanti F et al.Laie onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus.J Neurol Neurosurg Psychiatry. 1994; 57: 977-979Crossref PubMed Google Scholar, 10Harding AE Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia.J Neurol Neurosurg Psychiatry. 1981; 44: 503-508Crossref PubMed Google Scholar, 11Ragno M De Michele G Cavalcanti F et al.Broadened Friedreich's ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia.Neurology. 1997; 49: 1617-1620Crossref PubMed Google Scholar, 12Palau F De Michele G Vilchez JJ et al.Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich's ataxia locus on chromosome 9q.Ann Neurol. 1995; 37: 359-362Crossref PubMed Scopus (71) Google Scholar, 13Barbeau A Roy M Sadibelouiz M Wilensky MA Recessive ataxia in Acadians and “Cajuns.”.Can J Neural Sci. 1984; 11: 526-533PubMed Google Scholar, 14Keats BJ Ward LJ Shaw J Wickremasinghe A Chamberlain S “Acadian” and “classical” forms of Friedreich ataxia are most probably caused by mutations at the same locus.Am J Med Genet. 1989; 33: 266-268Crossref PubMed Google Scholar The size of the GAA expansion in late-onset FA is shorter, ranging from 120 to 156.9De Michele G Fitla A Cavalcanti F et al.Laie onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus.J Neurol Neurosurg Psychiatry. 1994; 57: 977-979Crossref PubMed Google Scholar, 10Harding AE Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia.J Neurol Neurosurg Psychiatry. 1981; 44: 503-508Crossref PubMed Google Scholar, 11Ragno M De Michele G Cavalcanti F et al.Broadened Friedreich's ataxia phenotype after gene cloning: minimal GAA expansion causes late-onset spastic ataxia.Neurology. 1997; 49: 1617-1620Crossref PubMed Google Scholar The expansion lengths in the FARR are similar to those in classic FA.8Epplen C Epplen JT Frank G Milerski B Santos KJ Schols L Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene.Hum Genet. 1997; 99: 834-836Crossref PubMed Scopus (91) Google Scholar, 15Montermini L Richter A Morgan K et al.Phcnotypic variability in Friedreich ataxia: role of the associated GAA triplet repeal expansion.Ann Neurol. 1997; 41: 675-682Crossref PubMed Scopus (164) Google Scholar The reduction of the normal frataxin in FA likely leads to the clinical manifestations, but there is debate about the manner in which this occurs. Since frataxin is a nuclearencoded mitochondrial protein, frataxin mutations may affect mitochondrial DNA repair or replication.” Frataxin levels are reduced because of the expansion, and this in turn may affect mitochondrial DNA repair or function.2Bidichandani SI Ashizawa T Patel PI The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.Am J Hum Genet. 1998; 62: 111-121Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 16Campuzalo V Montermini L Lutz Y et al.Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.Hum Mol Genet. 1997; 6: 1771-1780Crossref PubMed Scopus (381) Google Scholar, 17Gibson TJ Koonin EV Musco G Pastore A Bork P Friedrcich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction.Trends Neurosci. 1996; 19: 465-468Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar The FA gene mutation may also lead to abnormal iron accumulation within the mitochondria, resulting in increased production of toxic free radicals, since a frataxin homologue is known to be involved with iron homeostasis in the mitochondria.18Babcock M de Silva D Oaks R et al.Regulation of mitochondrial iron accumulation by Yfhlp, a putative homolog of frataxin.Science. 1997; 276: 1709-1712Crossref PubMed Scopus (578) Google Scholar, 19Priller J Schewer CR Faber PW MacDonald ME Young AB Frataxin gene of Friedreich's ataxia is targeted to mitochondria.Ann Neurol. 1997; 42: 265-269Crossref PubMed Scopus (75) Google Scholar, 20Foury F Cazzalini O Deletion of the yeast homologue of the human gene associated with Friedreich's ataxia elicitsiron accumulation in mitochondria.FEBS Let. 1997; 411: 373-377Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Finally, a widespread alteration in cellular phospholipid metabolism may occur in FA; this is supported by findings of reduced phospholipid levels in the cerebellar and occipital cortices.21Eder K Kish SJ Kirchgessner M Ross BM Brain phospholipids and fatty acids in Friedreich's ataxia and spinoccrebellar atrophy type-I.Mov Disord. 1998; 13: 813-819Crossref PubMed Scopus (11) Google Scholar Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive disorder that presents with an FA-like phenotype. Although the exact incidence is unknown, AVEO is rare. Individuals with vitamin E deficiency due to associated gastrointestinal or malabsorptive syndromes are excluded from this diagnosis classically (although their symptoms may be similar). The symptoms begin in childhood or adolescence (in persons 4 to 18 years), consisting of progressive ataxia, dysarthria, areflexia, sensory loss, ophthalmoplegia, retinitis pigmentosa, generalized muscle weakness, extensor plantar responses, and, sometimes, cardiomyopathy.22Harding AE Matthews S Jones S Ellis CJ Booth IW Muller DP Spinoccrebellar degeneration associated with a selective defect of vitamin E absorption.N Engl J Med. 1985; 313: 32-35Crossref PubMed Google Scholar Ataxia with isolated vitamin E deficiency has been linked to chromosome 8q 13; 3 frameshift mutations in the TTP 1 gene coding for α-tocopherol transfer protein have been identified as pathogenic, and a point mutation (histidine to glutamine substitution) at position 101 of the TTP 1 gene has also been reported (Table 1).23Ben Hamida C Docrflingcr N Belal S et al.Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping.Nat Genet. 1993; 5: 195-200Crossref PubMed Scopus (130) Google Scholar, 24Yokola T Shiojiri T Gotoda T et al.Friedreich-like ataxia with retinitis pigmentosa caused by the HislolGln mutation of the alpha-tocopherol transfer protein gene.Ann Neurol. 1997; 41: 826-832Crossref PubMed Scopus (76) Google Scholar One of these, a 744delA mutation, accounts for 68% of TTP 1 gene mutations in North Africa and Italy, areas in which populations may be related genetically. The α-tocopherol transfer protein incorporates α-tocopherol into lipoproteins in the liver, and this process is impaired in AVED. Since vitamin E is an antioxidant, its deficiency may lead to neuronal degeneration through cell damage from excess free radicals. Treatment, with α-tocopherol acetate (vitamin E) can arrest or reverse the ataxia syndrome. Because AVED is treatable, a high level of suspicion should exist for this disorder, especially in those with a phenotype resembling FA but without the F A mutation. Without treatment, patients are usually wheelchairbound by their third decade of life. The incidence of early-onset cerebellar ataxia with retained reflexes (EOCARR) is 1 in 48,000 live births. Like FA, EOCARR begins in the first or second decade of life, but it is distinguished from FA clinically by retained muscle stretch reflexes as well as by the absence of optic atrophy, cardiac pathology, diabetes, and severe skeletal abnormalities. Early-onset cerebellar ataxia with retained reflexes is similar to FARR, except that patients with EOCARR develop cerebellar atrophy (instead of spinal atrophy) and rarely develop sensory neuropathy.4Geoffroy G Barbeau A Breton G et al.Clinical description and rocntgcnologic evaluation of patients with Friedreich's ataxia.Can J Neural Sci. 1976; 3: 279-286PubMed Google Scholar, 25Hentati F Mrissa N Zouari M Belal S Ben Hamida C Ben Hamida M Exclusion of genetic linkage between autosomal recessive hereditary ataxia with brisk knee and absent ankle reflexes and Friedreich's ataxia phenotypes loci [abstract].Newrology. 1997; 48: AI78Google Scholar Other signs include impaired ocular saccades, spasticity of the lower limbs, brisk patellar reflexes, extensor plantar responses, and impairment of proprioception. The duration of symptoms from onset to death is usually less than 10 years. Linkage studies have excluded the FA and AVED gene loci.25Hentati F Mrissa N Zouari M Belal S Ben Hamida C Ben Hamida M Exclusion of genetic linkage between autosomal recessive hereditary ataxia with brisk knee and absent ankle reflexes and Friedreich's ataxia phenotypes loci [abstract].Newrology. 1997; 48: AI78Google Scholar Higgins et a26Higgins JJ Morton DH Palronas N Nec LE An aulosomal recessive disorder with posterior column ataxia and retinitis pigmentosa.Neurology. 1997; 49: 1717-1720Crossref PubMed Google Scholar described 6 patients from a large German-Swiss kindred with an autosomal recessive disorder of ataxia and retinitis pigmentosa that is not allelic to FA. This disorder begins during early childhood, with proprioceptive sensory loss and concentric contraction of the visual fields. By the third decade of life, blindness, severe sensory ataxia, achalasia, scoliosis, and inanition develop. Spinal cord magnetic resonance imaging (MRI) reveals a hyperintense signal in the posterior columns. The molecular basis is unknown. Infantile-onset SCA, an autosomal recessive ataxic syndrome, has been reported in a genetically isolated Finnish population and presents with cerebellar ataxia, sensory neuropathy, hyporeflexia, hypotonia, athetosis, deafness, ophthalmoplegia, optic atrophy, and seizures.27Nikali K Koskinen T Suomalainen A Pihko H Peltonen L Infantile onset spinocerebellar ataxia represents an allelic disease distinct from olher hereditary ataxias.Pediatr Rcs. 1994; 36: 607-612Crossref Google Scholar Primary hypogonadism may be seen among female patients. Brain MRI may show cerebellar cortical atrophy, olivopontocerebellar atrophy, or spinocerebellar atrophy.28Koskinen T Valanne L Ketonen LM Pihko H Infantile-onset spinocerebellar ataxia: MR and CT findings.AJNR Am J Neuroradial. 1995; 16: 1427-1433PubMed Google Scholar The gene locus for infantile-onset SCA is on chromosome 10q23.3-24.1,29Nikali K Suomalainen A Terwilliger J Koskinen T Weissenbach J Peltonen L Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus.Am J Hum Genet. 1995; 56: 1088-1095PubMed Google Scholar within the region coding for the neurofilament protein 66.30Chan SO Peng D Chiu FC Heterogeneous expression of ncurofilamenl proteins in forebrain and cerebellum during development: clinical implications for spinocerebellar ataxia.Brain Res. 1997; 775: 107-118Crossref PubMed Scopus (9) Google Scholar The myoclonus-ataxia syndromes include progressive myoclonic ataxia (PMA) and progressive myoclonic epilepsy (PME). (Because of the frequent and prominent occurrence of seizures in these disorders, they are also often classified among the epilepsies.) Progressive myoclonic ataxia and PME are also known as Ramsay Hunt syndrome and Unverricht-Lundborg disease (Baltic myoclonus or Mediterranean myoclonus), respectively. Progressive myoclonic epilepsy was originally described in Finland (incidence, 1 in 20,000 persons).31Leber S Progressive myoclonus epilepsy.in: Dodson WE Pellock JM Pediatrie Epilepsy: Diagnosis and Therapy. Demos, New York, NY1993: 171-181Google Scholar, 32Malafosse A Lehesjoki AE Genton P et al.Identical genetic locus for Baltic and Mediterranean myoclonus.Lancet. 1992; 339: 1080-1081Abstract PubMed Google Scholar Both PMA and PME are slowly progressive autosomal recessive disorders occurring in late childhood or early adulthood. Generalized seizures and dementia are prominent in PME, whereas severe myoclonus of cortical origin and progressive ataxia are prominent in PMA. Linkage analysis in several Finnish and Mediterranean families has shown that the gene for PME (EPM1) is on the long arm of chromosome 21q22.3.32Malafosse A Lehesjoki AE Genton P et al.Identical genetic locus for Baltic and Mediterranean myoclonus.Lancet. 1992; 339: 1080-1081Abstract PubMed Google Scholar, 33Virtaneva K D'Ama E Miao J et al.Unstable minisaiellile expansion causing recessively inherited myoclonus epilepsy, EPM1.Nat Genet. 1997; 15: 393-396Crossref PubMed Scopus (139) Google Scholar It encodes for a cysteine protease inhibitor, cystatin B.34Lalioli MD Mirotsou M Buresi C et al.Identification of mutations in cystatin B. the gene responsible for the Unvemcht-Lundborg type of progressive myoclonus epilepsy (EPM1).Am J Hum Genet. 1997; 60: 342-351PubMed Google Scholar Most patients who have been characterized with PME have an unstable dodecamer minisatellite repeat expansion in the promoter region of the cystatin B gene; however, insertions, deletions, and missense mutations in the cystatin B gene have also been identified.33Virtaneva K D'Ama E Miao J et al.Unstable minisaiellile expansion causing recessively inherited myoclonus epilepsy, EPM1.Nat Genet. 1997; 15: 393-396Crossref PubMed Scopus (139) Google Scholar, 34Lalioli MD Mirotsou M Buresi C et al.Identification of mutations in cystatin B. the gene responsible for the Unvemcht-Lundborg type of progressive myoclonus epilepsy (EPM1).Am J Hum Genet. 1997; 60: 342-351PubMed Google Scholar, 35Pennacchio LA Lehesjoki AE Slone NE et al.Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EOM1).Scienee. 1996; 271: 1731-1734Crossref PubMed Google Scholar, 36Lafreniere RG Rochefort DL Chretien N et al.Unstable insertion in the 5′ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM).Nat Genet. 1997; 15: 298-302Crossref PubMed Scopus (125) Google Scholar The manner in which the mutation or expansion leads to the clinical phenotype remains unclear. Holmes37Holmes G A form of familial degeneration of the cerebellum.Brain. 1907; 30: 466-489Crossref Scopus (44) Google Scholar first described the association of familial cerebellar ataxia with hypogonadism, and numerous reports have appeared thereafter. The frequency is unknown, but the disorder is rare. The age at onset is usually in the fourth to sixth decade of life, although the disease may occur as early as the second decade and as late as the seventh decade. The hypogonadal syndrome can be primary or secondary, or, rarely, it may manifest as only sperm structural abnormalities.38Fok AC Wong MC Cheah JS Syndrome of cerebellar ataxia and hypogonadolrophic hypogonadism: evidence for pituitary gonadotrophin deficiency.J Neurol Neurosurg Psychiatry. 1989; 52: 407-409Crossref PubMed Google Scholar, 39Malandrini A Villanova M Piomboni P et al.Ultrastruciural sperm abnormalities and cerebellar atrophy; docs a correlation exist? report of two cases without endocrine hypogonadism.J Submicrosc Cytol Paihol. 1993; 25: 371-375PubMed Google Scholar Brain imaging findings include atrophy of the cerebellum and, less commonly, of the brain stem. Postmortem examination may show spinocerebelloolivary degeneration or a complex spinodentate-brainstem atrophy. A related but rare disorder, the BoucherNeuhauser syndrome, consists of familial spinocerebellar or cerebellar ataxia with hypogonadotropic hypogonadism and chorioretinal dystrophy.40Tojo K Ichinuse M Nakayama M et al.A new family of Boucher-Neuhauscr syndrome: coexistence of Holmes type cerebellar atrophy, hypogonadotropic hypogonadism and retino-choroidal degeneration: case reports and review of literaturc.EndocrJ. 1995; 42: 367-376Crossref Google Scholar The diagnosis is clinical; no molecular characterization exists to date. The Marinesco-Sjögren syndrome is a rare autosomal recessive disorder presenting in early childhood with cerebellar ataxia, congenital cataracts, hypotonia, progressive muscular weakness and atrophy, multiple skeletal abnormalities, hypogonadism, and mental retardation.41Marinesco G Draganesco S Vasiliu D Nouvelle maladie familiale caractérisée par une cataracte congénitale et un arrêt du développement somato-neuropsychique.Encephale. 1931; 26: 97-109Google Scholar Magnetic resonance imaging may show diffuse brain atrophy, involving primarily the white matter of the cerebrum, cerebellum, brain stem, and cervical spinal cord.42Bromberg MB Junck L Gebarski SS McLean MJ Gilman S The Marinesco-Sjögren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fIuoro-2-deoxy-D-glucose and positron emission tomography.Arch Neurol. 1990; 47: 1239-1242Crossref PubMed Google Scholar The neuropathological findings include pronounced cerebellar cortical atrophy with vacuolated or binucleated Purkinje cells.43Todorov A Le syndrôme de Marinesco-Sjögren: premiêre étude analomo-clinjque.J Gener Hum. 1965; 14: 197-233PubMed Google Scholar Electron microscopy shows numerous enlarged lysosomes with inclusion bodies, suggesting that Marinesco-Sjögren syndrome may be a lysosomal storage disorder.44Walker PD Blilzer MG Shapira E Marinesco-Sjögren syndrome; evidence for a lysosomal storage disorder.Neurology. 1985; 35: 415-419Crossref PubMed Google Scholar The disease may represent a type of hypergonadotropic hypogonadism.45Skrc H Berg K Linkage studies on Marinesco-Sjögren syndrome and hypcrgonadotropic hypogonadism.Clin Genet. 1977; 11: 57-66PubMed Google Scholar Behr syndrome is a rare autosomal recessive disorder that presents during early childhood with progressive ataxia, optic atrophy, mental retardation, and corticospinal tract dysfunction (weakness and spasticity).46Horoupian DS Zucker DK Moshe S Peterson HD Behr syndrome; a clinicopalhologic report.Neurology. 1979; 29: 323-327Crossref PubMed Google Scholar, 47Landrigan PJ Berenberg W Bresnan M Behr's syndrome: familial optic atrophy, spastic diplegia and alaxia.Dev Med Child Neurol. 1973; 15: 41-47Crossref PubMed Google Scholar Neuronal loss and gliosis occur in the optic nerve, lateral geniculate body, thalamus, and globus pallidus, and numerous axonal spheroids are seen in the neuropil. Diffuse symmetrical white matter abnormalities may be detected on MRI.48Marzan KA Barron TF MRI abnormalities in Behr syndrome.Pediatr Neurol. 1994; 10: 247-248Abstract Full Text PDF PubMed Scopus (8) Google Scholar Molec