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Spinocerebellar ataxia type-7 (SCA7) is a cytosine-adenine-guanine (CAG) repeat polyglutamine disorder characterized by progressive degeneration of the cerebellum, brainstem, spinal cord, and retina. Clinical features include progressive ataxia, visual loss, pyramidal weakness, sensory impairment, and dementia. Among the autosomal dominant cerebellar ataxias, SCA7 is relatively common in Scandinavia and South Africa but rare worldwide and is not previously reported in Nigeria. In this study, we describe a family in Katsina State, Northwest Nigeria, with nine individuals across three generations affected by the SCA7 phenotype. Analysis of DNA from proband and two affected relatives revealed 39 CAG repeat expansions in one allele of ataxin-7 in each.
Ataxie spinocérébelleuse type de - 7 (SCA7) est une cytosine - adénine - guanine (CAG) Répétez polyglutamine trouble qui se caractérise par une dégénérescence progressive du cervelet, tronc cérébral, moelle épinière et la rétine. Les signes cliniques incluent une ataxie progressive, perte de la vue, faiblesse pyramidale, déficience sensorielle et la démence. Parmi les ataxies cérébelleuses autosomiques dominantes, SCA7 est relativement courante en Scandinavie et en Afrique du Sud, mais rare dans le monde entier et n’est pas déjà signalé au Nigeria. Dans cette étude, nous décrivons une famille dans l’Etat de Katsina, nord-ouest du Nigeria, avec neuf personnes à travers trois générations touchées par le phénotype SCA7. Analyse de l’ADN de proband et deux parents touchés a révélé 39 extensions répétées CAG dans un allèle d’ataxine-7 chacune.
Spinocerebellar ataxia type-7 (SCA7) is one of the polyglutamine expansion autosomal dominant cerebellar ataxias. It is characterized by retinal photoreceptor degeneration and neuronal loss in the cerebellum, posterior columns, and anterior horns of the spinal cord. The underlying abnormality is a trinucleotide cytosine-adenine-guanine (CAG) repeat expansion in the ataxin-7 (ATXN7) gene on chromosome 3p. In Europe, SCA7 contributes 1–12% of all dominantly inherited SCAs, which as a group affects approximately 3/100,000 Europeans. The only autosomal dominant SCA described in Nigeria was SCA3, also known as Machado–Joseph disease, which was detected in a family in Calabar, Cross River State. We herein describe nine members of a family in Northwest Nigeria affected by SCA7, which was confirmed in three individuals through DNA analysis. We then review relevant literature on the subject.
A 52-year-old man presented at the National Hospital with 5 years history of progressive imbalance of gait, speech and memory impairment, and occasional urinary incontinence. He has never smoked tobacco or taken alcohol. His parents were first cousins from the Hausa ethnic group. His 78-year-old father is alive and well. His 70-year-old mother developed unsteady gait and dysphagia at age 55 years and is now bedridden and blind. His maternal aunt had died of a similar illness at age 39 years.
Of his 12 siblings, all four sisters are alive and well, but five of eight brothers died [Figure 1]. Three brothers died of unrelated causes, but one died at age 19 years following speech and swallowing difficulties while another one developed frequent falls, dementia, and blindness at age 27 years and died at 45 years. One brother is apparently healthy at age 54 years, but two others aged 42 and 43 years both suffer progressive imbalance of gait. The patient is married to one wife and has had seven children, of whom three have died. One son had frequent falls, seizures, abnormal speech, and blindness at age 8 years and died 3 years later. A daughter died of neonatal sepsis, while another daughter had unsteady gait and speech and swallowing difficulties at 2 years and died at 6 years.
On examination, the patient was oriented and scored 28/30 on the Mini-Mental State Examination Scale. He had dysarthria and slow saccades on eye movement. Visual acuity was 6/18 in both eyes, and fundoscopy showed bilateral peripapillary atrophy. He had global hyperreflexia, bilateral ankle clonus, and extensor plantar responses. Muscle power was 5/5 in all limbs. He had a glove-and-stocking sensory loss and bilateral cerebellar signs and scored 16/40 on the Scale for the Assessment and Rating of Ataxia.
His mother and 42-year-old brother both had visual impairment, ataxia, and sensory loss on examination. Investigations performed on the patient including a full blood count, serum chemistry, fasting glucose, lipid profile, thyroid function tests, serum Vitamins E and B12 levels, and electrocardiogram were all normal. We suspected a mitochondrial encephalopathy to keep in view SCA7 and von-Hippel–Lindau syndrome. When brain magnetic resonance imaging revealed brainstem atrophy with normal spinal cord, cerebellum, and cerebral hemispheres [Figure 2], we diagnosed SCA7 and tested for CAG repeat expansions at the SCA1, 2, 3, 6, and 7 loci on the proband, his mother and his 42-year-old brother.
DNA was extracted from peripheral blood and analyzed by polymerase chain reaction and capillary electrophoresis at the Molecular Diagnostics Laboratory of the National Health Laboratory Service in Cape Town, South Africa. Each of the three samples tested showed expansion mutations of 39 repeats at the SCA7 (ATXN7) gene locus, where one normal allele and one fully expanded allele (10/39) were observed.
Our patient and eight family members had clinical features of SCA7 and analysis of DNA from three kindred-revealed expanded mutations at the ATXN7 locus. To our knowledge, this is the first confirmed report of SCA7 in a Nigerian family.
The normal allele of ATXN7 carries 7–35 CAG repeats, and SCA7 results when repeat numbers exceed 36. The physiological function of ATXN7 is not well understood, though it is believed to harbor a zinc-binding domain which promotes histone acetylation and deubiquitination, gene transcription, and export of messenger RNA from the nucleus. Although SCA7 is rare worldwide, it is the most common subtype of the autosomal dominant cerebellar ataxias in Sweden and Finland. Among Black South Africans, SCA7 constitutes 59% of all genetically verified autosomal dominant cerebellar ataxias, a prevalence rate higher than that seen elsewhere. As in Scandinavia, a shared haplotype was identified among the Black South African SCA7 population, suggesting a common founder effect. Clinical features of SCA7 include ataxia, dysarthria, pyramidal signs, ophthalmoparesis, and blindness.[6,8] Some patients may have sensory loss, autonomic dysfunction, cognitive impairment, and dementia, especially in advanced disease.
Expanded CAG repeats are unstable and tend to expand further, particularly during paternal transmissions. Thus, larger repeat sizes are seen in later generations of an affected family, a phenomenon termed genetic anticipation. Since an inverse relationship exists between CAG repeat size and age of disease onset, disease manifests earlier in successive generations. The CAG repeat size also contributes to the variation in clinical features. In a Swedish cohort, visual impairment was the common initial symptom in patients with 59 repeats or more, while ataxia predominated in those with fewer repeats. The longest repeat length of 230 was found in a child with disease onset at 3 months. We have observed anticipation in this family, where the proband and his siblings developed disease after adolescence, his mother during her sixth decade, and his children during childhood.
The management of SCA7 entails supportive care and counseling. Dysphagia may require a gastrostomy, while obese patients may need to lose weight to improve mobility. Physical and speech therapy can help improve quality of life. An emerging therapeutic strategy is RNA interference therapy, which involves selective silencing of mutant ATXN7 through inhibition of its messenger RNA. This novel approach has yielded promising results in experiments on human cell cultures.
There are no conflicts of interest.
We express gratitude to former House of Representatives Member Hon. Aishatu Dahiru Ahmed for personally funding our patients’ genetic tests in South Africa.