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Fulltext A family with hereditary ataxia

Tan CT

Med J Malaysia, 1980 Dec;35(2):134-8.
PMID: 7266406

An Indian family with four members having hereditary ataxia was presented. The inheritance was most likely autosomal dominant. The onset was at adult life. The main disability was cerebellar ataxia with pyramidal tract sign found at physical examination. Electroencephalography and nerve conduction study were abnormal in two cases where they were done. The clinical feature correspond to an intermediate form of hereditary ataxia.

Matched MeSH terms: Cerebellar Ataxia/genetics*
Malaysian siblings with friedreich ataxia and chorea: a novel deletion in the frataxin gene

Spacey SD, Szczygielski BI, Young SP, Hukin J, Selby K, Snutch TP

Can J Neurol Sci, 2004 Aug;31(3):383-6.
PMID: 15376485

BACKGROUND: Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype.
OBJECTIVE: To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1.
SETTING: Tertiary referral university hospital setting.
PATIENTS AND METHODS: A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact.
RESULTS: Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele.
CONCLUSIONS: We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.

Matched MeSH terms: Friedreich Ataxia/genetics*
Molecular and clinical investigation of Iranian patients with Friedreich ataxia

Salehi MH, Houshmand M, Aryani O, Kamalidehghan B, Khalili E

Iran Biomed J, 2014;18(1):28-33.
PMID: 24375160

BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by guanine-adenine-adenine (GAA) triplet expansions in the FXN gene. Its product, frataxin, which severely reduces in FRDA patients, leads to oxidative damage in mitochondria. The purpose of this study was to evaluate the triple nucleotide repeated expansions in Iranian FRDA patients and to elucidate distinguishable FRDA clinical differences in these patients.
METHODS: A number of 22 Iranian patients (8 females and 14 males) from 16 unrelated families were studied. DNA was extracted from the peripheral blood of patients. The frequency and length of (GAA)n repeats in intron 1 of the FXN gene were analyzed using long-range PCR. In this study, the clinical criteria of FRDA in our patients and the variability in their clinical signs were also demonstrated.
RESULTS: An inverse relationship was observed between GAA repeat size and the age of onset. Although some distinguishable clinical features (such as limb ataxia and lower limb areflexia) were found in our patients, 90-95% of them had extensor plantar response and dysarthria. The results showed only one positive diabetes patient and also different effects on eye movement abnormality among our patients.
CONCLUSION: The onset age of symptoms showed a significant inverse correlation with allele size in our patients (P>0.05). Based on comparisons of the clinical data of all patients, clinical presentation of FRDA in Iranian patients did not differ significantly from other FRDA patients previously reported.

Matched MeSH terms: Ataxia/genetics; Friedreich Ataxia/genetics*
Fulltext Gene expression profiling of mitochondrial oxidative phosphorylation (OXPHOS) complex I in Friedreich ataxia (FRDA) patients

Salehi MH, Kamalidehghan B, Houshmand M, Yong Meng G, Sadeghizadeh M, Aryani O, et al.

PLoS One, 2014;9(4):e94069.
PMID: 24705504 DOI: 10.1371/journal.pone.0094069

Friedreich ataxia (FRDA) is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein. Gene expression studies provide insights into disease pathogenicity and identify potential biomarkers, an important goal of translational research in neurodegenerative diseases. Here, using real-time PCR (RT-PCR), the expression profiles of mitochondrial (mtDNA) and nuclear DNA (nDNA) genes that encode for the mitochondrial subunits of respiratory oxidative phosphorylation (OXPHOS) complex I in the blood panels of 21 FRDA patients and 24 healthy controls were investigated. Here, the expression pattern of mtDNA-encoded complex I subunits was distinctly different from the expression pattern of nDNA-encoded complex I subunits, where significant (p<0.05) down-regulation of the mitochondrial ND2, ND4L, and ND6 complex I genes, compared to controls, were observed. In addition, the expression pattern of one nDNA-encoded gene, NDUFA1, was significantly (p<0.05) down-regulated compared to control. These findings suggest, for the first time, that the regulation of complex I subunit expression in FRDA is complex, rather than merely being a reflection of global co-regulation, and may provide important clues toward novel therapeutic strategies for FRDA and mitochondrial complex I deficiency.

Matched MeSH terms: Friedreich Ataxia/genetics*
Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore

Zhao Y, Tan EK, Law HY, Yoon CS, Wong MC, Ng I

Clin Genet, 2002 Dec;62(6):478-81.
PMID: 12485197

We report the prevalence and ethnic differences of autosomal-dominant cerebellar ataxia (ADCA) in Singapore. Amongst 204 patients with ataxia who underwent genetic testing for dentatorubral-pallidoluysian atrophy (DRPLA) and for spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7, 8, 10 and 12, 58 (28.4%) patients from 36 families tested positive. SCA 3 was identified in 31 (53.4%) patients from 15 families, SCA 2 in 17 (29.3%) patients from 12 families and SCA 1 in four (6.9%) patients from four families. Other SCA subtypes were rare. SCA 2 was the only subtype identified amongst ethnic Malay and ethnic Indian families. The estimated prevalence of ADCA in Singaporean families was at least 1 : 27,000. Based on the history and ancestry of Singaporeans, our study supported a founder effect for specific SCA subtypes and the association of ethnicity-specific SCA subtypes. Our findings suggest that SCA 2 is relatively common amongst the Malay race and that priority testing for SCA 3 and SCA 2 for ethnic Chinese, and SCA 2 for ethnic Malay, may be cost effective and relevant for the region.

Matched MeSH terms: Cerebellar Ataxia/genetics*
The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias

Giunti P, Sweeney MG, Spadaro M, Jodice C, Novelletto A, Malaspina P, et al.

Brain, 1994 Aug;117 ( Pt 4):645-9.
PMID: 7922453

Affected members of 73 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCAs) were investigated for the trinucleotide (CAG) repeat expansion which is found in pedigrees exhibiting linkage to the SCA1 locus on chromosome 6. Most of the families were too small for linkage analysis. The mutation was only found in ADCA type I, in 19 out of 38 such kindreds investigated (50%). It was slightly more common in Italian (59%) than British (50%) families, and was also found in Malaysian, Bangladeshi and Jamaican kindreds. Overall, ADCA type I patients with the expansion had a lower incidence of hyporeflexia and facial fasciculation than those without. The trinucleotide expansion was not found in eight families with ADCA and maculopathy or 24 kindreds with a pure type of ADCA, confirming that these syndromes are genetically distinct. It was also not detected in 12 patients with sporadic degenerative ataxias. DNA analysis for the SCA1 mutation is useful diagnostically in single patients or small families, and can be used for presymptomatic testing where appropriate.

Matched MeSH terms: Cerebellar Ataxia/genetics*
Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, et al.

Nat Genet, 2019 08;51(8):1222-1232.
PMID: 31332380 DOI: 10.1038/s41588-019-0458-z

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

Matched MeSH terms: Ataxia/genetics*