Recent Advances in the Genetics of Mitochondrial Encephalopathies

Mitochondrial encephalopathy, the most common neurometabolic disorder, may be caused by mutations in approximately 100 different genes and may present with various symptoms, such as seizures, ataxia, myopathy, cognitive impairment, blindness, and stroke. Fewer than 50% of patients with mitochondrial encephalopathy receive a molecular diagnosis, primarily because of the large degree of clinical and genetic heterogeneity among patients and the limited knowledge of the genes involved in mitochondrial function. Here we review the most recent discoveries of genes associated with mitochondrial disease with variable neuropathology. All these genes have been identified via homozygosity mapping or linkage analysis; however, advances in sequencing technology indicate that the future of genetic diagnosis and disease gene discovery likely lies in high-throughput sequencing.     

Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised α-fetoprotein

We describe three patients from two families with progressive spinocerebellar ataxia, peripheral neuropathy, raised alpha-fetoprotein (AFP) and hypercholesterolaemia. Two siblings had identical clinical features, with late childhood onset of symptoms and slow progression, requiring crutches to walk at ages 37 and 38 years. Another patient developed ataxia aged 13 years and became wheel-chair bound by 20 years of age. Although they all had raised serum AFP levels, their clinical, immunological, biochemical, cytogenetic and molecular genetic studies failed to support a diagnosis of Ataxia Telangiectasia. Extensive investigation including imaging, biochemical and genetic studies excluded other known ataxias. Their clinical features most closely resemble the phenotype of a single consanguineous Japanese family with four individuals affected by spinocerebellar ataxia, peripheral neuropathy, raised AFP and hypercholesterolaemia. Homozygosity mapping has identified a locus in this Japanese family at 9q34. Haplotype analysis of our cases demonstrated possible linkage to 9q34, suggesting these may be the first Caucasian families described with this disorder.     

The clinical characteristics of spinocerebellar ataxia 36: A study of 2121 Japanese ataxia patients

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes. ? 2012 Movement Disorder Society.     

The complex clinical and genetic classification of inherited ataxias. II. Autosomal recessive ataxias

Autosomal recessive ataxias are a heterogeneous group of rare neurodegenerative diseases characterized by early onset cerebellar ataxia associated with various neurologic, ophthalmologic and systemic signs. In comparison with autosomal dominant ataxias, the group of recessive ataxias is less extensively characterized. In fact, only a few conditions have been genetically characterized. The pathogenesis of these forms is associated with a "loss of function" of specific cellular proteins involved in metabolic homeostasis, cell cycle, and DNA repair/protection processing. The two most common autosomal recessive ataxias, in European countries, are Friedreich's ataxia and ataxia telangiectasia. Other forms are much less frequent, and include ataxia with vitamin E deficiency, abetalipoproteinemia. Refsum's disease, spastic ataxia, infantile onset spinocerebellar ataxia, and ataxia with oculomotor apraxia. These pathological conditions, although extremely rare, have nevertheless to be carefully considered in differential diagnosis, not only for correct nosographical classification, but particularly, for specific prognostic and therapeutic implications. Some of these diseases exhibit a peculiar regional distribution. An updated review of the clinical, genetic, and pathogenic aspects of recessive ataxias is presented. Specific management problems with respect to diagnosis and genetic counseling are discussed.     

Practical clues for diagnosing WWOX encephalopathy

The WW domain‐containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early‐infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early‐onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly. Metabolic disease was excluded. Whole‐exome sequencing showed mutations in the WW domain‐containing oxidoreductase gene. Our findings extend the phenotypic traits of this aggressive epileptic encephalopathy, with persistent epileptic spasms and hypsarhythmia as a part of the electroclinical phenotype, demonstrating that microcephaly is not mandatory for diagnosis, even when associated with progressive cerebral atrophy. These mutations might be more frequent than expected among early‐onset epileptic encephalopathies. We present practical clues for the diagnosis of WWOX encephalopathy in order to avoid unnecessary investigations and ensure appropriate genetic counselling for the families.     

X-linked adrenoleukodystrophy: spinocerebellar variant.

The phenotypic variability in X-linked adrenoleukodystrophy (X-ALD) can be wide and varied. Rarely, it can present with clinical signs of spinocerebellar degeneration. There are very few reported cases of selective predominant white matter disease of the cerebellum in these patients. We report a patient with a rare variant of adult onset ALD who was previously diagnosed as spinocerebellar ataxia. He was a 24-year-old male who had delayed developmental milestones, developed signs of spinocerebellar degeneration (SCD) after 10 years of Addison's disease. Serial Magnetic Resonance Imaging (MRI), revealed cerebellar and pontine white matter disease but sparing the cerebral cortex and supratentorial white matter. His diagnosis of X-ALD was subsequently confirmed by the elevated serum very long chain fatty acids. This patient illustrates the unusual clinical presentation and imaging features of X-ALD and the importance of considering X-ALD in the clinical context of spinocerebellar degeneration. Early recognition of this rare variant would allow proper genetic counselling and institution of dietary therapy and/or bone marrow transplantation.     

A Japanese family with Machado-Joseph disease characterized by initial emaciation and myoclonus

We describe a Japanese family with hereditary spinocerebellar ataxia characterized by initial emaciation and myoclonus. The proband first noted truncal ataxia, myoclonus in the shoulder and general emaciation at age 24. The other affected members of the family also had such emaciation in the early stage of the disease. The DNA analyses of the family revealed that the patients of the family are associated with the expansions of CAG repeats for Machado–Joseph disease (MJD) on the long arm of chromosome 14. Although the clinical features of MJD are very variable, general emaciation in an early stage of the disease and systemic myoclonus have not been documented. Because it is sometimes difficult to distinguish among hereditary spinocerebellar ataxias such as spinocerebellar ataxia type 1 (SCA1) or dentatorubropallidoluysian atrophy (DRPLA) by clinical features, a genetic examination provides better understanding of such a rare and ambiguous type of hereditary spinocerebellar ataxia.     

Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease

The autosomal dominant spinocerebellar ataxias are clinically and genetically a heterogeneous group of neurodegenerative disorders. Genetic studies have classified some of these disorders based on the mapping of their respective genes. The gene for Machado-Joseph disease, one type of spinocerebellar ataxia, has been mapped to the long arm of chromosome 14q24.3-ter. The gene for another spinocerebellar ataxia, which is clinically distinct from Machado-Joseph disease, has been also localized to the same region on 14q and has been named type 3 spinocerebellar ataxia. Recently, expansions of a CAG trinculeotide repeat in a novel gene on chromosome 14q32.1 were shown in 11 patients affected with Machado-Joseph disease. In this study, we analyzed the DNA samples from 103 individuals representing 42 independent families with dominantly inherited ataxia to determine whether any had the Machado-Joseph disease mutation. The Machado-Joseph disease CAG expansion was detected in 5 of these 42 families. Sixteen affected individuals displayed a normal allele containing 14 to 31 CAG repeats and an expanded allele ranging between 66 and 79 CAG repeats. Seven asymptomatic individuals showed an allele ranging between 67 and 80 CAG repeats. Two of these families had a phenotype consistent with Machado-Joseph disease while the other 3 had clinical features of type 3 spinocerebellar ataxia. These data suggest that a single locus at 14q32.1 is responsible for two forms of spinocerebellar ataxia, spinocerebellar ataxia type 3 and Machado-Joseph disease, and that this locus may account for approximately 11% of this group of dominantly inherited ataxias.     

Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.     

Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11-12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.     

Spinocerebellar ataxia type 3 presenting as an L-DOPA responsive dystonia phenotype in a Chinese family

The clinical spectrum of spinocerebellar ataxia 3 (SCA 3) disease is wide and varied. We describe a Chinese patient with a mutation at the SCA 3 locus with clinical features of levodopa-responsive dystonia. The family history was suggestive of being autosomally dominant. Levodopa responsiveness though rare has been described in families with features of parkinsonism. Noteworthy is the relatively late onset of disease (>40 years) possibly explained by the low number of affected alleles at 59, the usual range being from 62 to 86, with the lowest recorded number at 56. This expands the wide and varied phenotypic manifestations of SCA 3, and highlights the observation that features suggestive of levodopa-responsive dystonia (DRD) such as focal dystonia, gait difficulty with diurnal fluctuation of symptoms, and a marked response to low doses of levodopa can be presenting features of SCA 3. SCA 3 should be considered a differential diagnosis in adult patients who present with DRD phenotype and with a positive family history.     

Italian Huntington disease patients-data and tissue bank

Abstract. We have collected clinical and genetic data on Huntington disease (HD) patients and their families over the last 5 years at the Unit of Neurogenetics, IRCCS Neuromed of Pozzilli (IS), Italy. Data on 854 mutation carriers are included in the data bank, together with a large number of DNA samples, blood, and other tissues. In particular, lymphoblastoid cell lines from 100 patients, including subjects carrying very rare genetic conditions (CAG mutation homozygosity, juvenile and infantile onset, pre-mutations) have been established. For all these initiatives ethical approval from the bioethics committee was obtained. We wish to extend this initiative to all families, investigators, and institutions within and, possibly outside, the Italian border in an attempt to enlarge the bank and to institute a HD Research Roster.     

Spinocerebellar ataxia type 2 in a Turkish family

Autosomal dominant spinocerebellar ataxias are neurodegenerative disorders that generally present in adulthood. Due to extreme expansion of the repeat size during spermatogenesis, they can also be observed in childhood. The diagnosis in childhood is very difficult in the absence of family history. Here we describe an 8-year-old girl with spinocerebellar ataxia type 2 who presented with progressive ataxia, cognitive deficits, and dysarthria. A detailed family history exhibited similarly affected cases on the paternal side. Molecular testing for spinocerebellar ataxia type 2 revealed abnormal "cytosineadenine-guanosine" expansion in all affected family members. The number of cytosine-adenine-guanosine repeats in the index case was 70. The mean size of expansion in the relatives of the patient was 42 (39-46). This finding explains the early onset of symptoms in the index case.     

HLA-linked spinocerebellar ataxia: a clinical and genetic study of large Italian kindreds

Five families with late onset autosomal dominant spinocerebellar ataxia, were studied. Linkage between the disease and HLA loci on the short arm of chromosome 6 was shown in the two largest pedigrees. Clinical study of 26 patients and neuropathological study in one are reported. The disease was characterized by cerebellar and pyramidal involvement variably associated with cranial nerve and peripheral nervous system disorders. A remarkable concordance of the main clinical features was observed in patients with similar disease duration. Comparison with previous reports of HLA-linked spinocerebellar ataxia kindreds showed differences in clinical phenotypes. Although these might be due to genetic variation, the hypothesis is suggested that the phenotype might appear more homogeneous if disease duration is taken into account.     

LINKAGE TO CHROMOSOME 13Q11-12 OF AN AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA IN A TUNISIAN FAMILY

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11-12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.     

Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population.

Autosomal dominant spinocerebellar ataxias (AD-SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5'-untranslated region of the puratrophin-1 gene was found to be associated with one type of AD-SCA linked to chromosome 16q (16q-SCA). To obtain further insight into the contribution of the C-to-T substitution in the puratrophin-1 gene to the clinical and genetic characteristics of patients with 16q-SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C-to-T substitution in the puratrophin-1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q-SCA was 59.1 (range, 46-77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD-SCA subtype, considering the effects of age at onset. In the 686 AD-SCA families, SCA6 and Machado-Joseph disease/SCA3 are frequent subtypes, followed by dentatorubral-pallidoluysian atrophy and 16q-SCA. 16q-SCA is not a rare subtype of Japanese AD-SCA, particularly in patients with ages at onset over 60.     

Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays

The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.     

Investigation of recessive ataxia loci in patients with young age of onset

Autosomal recessive cerebellar ataxias are a phenotypically and genetically heterogeneous group of diseases. Major forms can be distinguished on the basis of clinical signs, age of onset, biochemical parameters or genotypes. To develop rational diagnostic strategies, phenotypic information, e.g., age of onset combined with population-specific disease frequencies could be highly favourable. We tested this hypothesis for single candidate loci and mutations in North European ataxia patients with juvenile and early adult onset. While we could prove that Friedreich ataxia (FRDA) is frequent in Germany, only few patients with ataxia-oculomotor apraxia type 1 (AOA1) and type 2 (AOA2) were diagnosed. The frequency of the mitochondrial recessive ataxia syndrome (MIRAS) and the infantile onset spinocerebellar ataxia (IOSCA) in this population remains unknown since no case with the common mutation of the corresponding gene was detected.