Autosomal Recessive Cerebellar Ataxia Research Articles

Autosomal recessive cerebellar ataxia with bull’s-eye macular dystrophy

PURPOSE: In 1980, we published in the American Journal of Ophthalmology two siblings with hereditary ataxia and atrophic maculopathy. The report is cited in the literature as autosomal dominant cerebellar ataxia with retinal degeneration. The purpose of the present study is to document the progression of the neurodegenerative disorder and to review the diagnosis. DESIGN: Observational case report. METHODS: Twenty years after the original publication, the 52-year-old male patient had new ocular and neurologic examinations, fluorescein angiography, molecular genetic analysis, and biochemical testing. RESULTS: Fluorescein angiography showed marked progression of the macular dystrophy to a bull’s-eye configuration. Genetic analysis of the patient did not show CAG trinucleotide repeat expansion in the various spinocerebellar ataxia genes. This excludes the diagnosis of autosomal dominant cerebellar ataxia with macular degeneration (ADCA type II) with mutation of the spinocerebellar ataxia 7 gene. Major causes of autosomal recessive cerebellar ataxia with retinal degeneration, including Friedreich ataxia and congenital disorders of glycosylation, were also excluded. CONCLUSION: The two patients, previously published in the American Journal of Ophthalmology by Eerola and coworkers, did not suffer from presently recognized disorders with cerebellar ataxia and retinal degeneration. The Eerola syndrome probably represents a separate neurodegenerative entity characterized by autosomal recessive cerebellar ataxia and progressive macular dystrophy with a bull’s-eye pattern.

A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

Nonprogressive autosomal recessive ataxia maps to chromosome 9q34‐9qter in a large consanguineous lebanese family

Congenital ataxias are a heterogeneous group of predominantly nonprogressive disorders characterized by hypotonia, developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We performed a genome-wide screen on a large inbred Lebanese family presenting a nonprogressive autosomal recessive congenital cerebellar ataxia associated with short stature (MIM 213200), already described by Mégarbané and colleagues.1 The disease locus was assigned to a 12.1 cM interval on chromosome 9q34-9qter between D9S67 and D9S312. Differential diagnosis with other hereditary ataxias linked to the same region is discussed.

Nonprogressive autosomal recessive ataxia maps to chromosome 9q34‐9qter in a large consanguineous lebanese family

Congenital ataxias are a heterogeneous group of predominantly nonprogressive disorders characterized by hypotonia, developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We performed a genome-wide screen on a large inbred Lebanese family presenting a nonprogressive autosomal recessive congenital cerebellar ataxia associated with short stature (MIM 213200), already described by Mégarbané and colleagues. The disease locus was assigned to a 12.1 cM interval on chromosome 9q34-9qter between D9S67 and D9S312. Differential diagnosis with other hereditary ataxias linked to the same region is discussed.

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.

Autosomal Recessive Cerebellar Ataxia with Oculomotor Apraxia (Ataxia‐Telangiectasia–Like Syndrome) Is Linked to Chromosome 9q34

Autosomal Recessive Cerebellar Ataxia with Oculomotor Apraxia (Ataxia‐Telangiectasia–Like Syndrome) Is Linked to Chromosome 9q34

Autosomal Recessive Cerebellar Ataxia with Oculomotor Apraxia (Ataxia-Telangiectasia–Like Syndrome) Is Linked to Chromosome 9q34

Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.

A review of the inherited ataxias: recent advances in genetic, clinical and neuropathologic aspects

Inherited ataxias are a heterogeneous group of disorders characterized by autosomal dominant and recessive inheritance. Recent advances in genetic research have resulted in an improved comprehension of their clinical presentation. Autosomal dominant cerebellar ataxias (ADCAs) include spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA); six of these have been found to be trinucleotide repeat disorders. Episodic ataxia, types 1 and 2, are at present recognized to be channelopathies, caused by point mutations. Friedreich's ataxia (FA) which is an autosomal recessive disorder, resulting from a a unique trinucleotide repeat, is now recognized to have a wide age of onset and clinical spectrum. Ataxia-telangiectasia (AT), also an autosomal recessive cerebellar ataxia, is characterized by immunodeficiency. In this article, the genetic and clinical characteristics of these diseases are reviewed in detail.

Neuropathologic abnormalities of the brain in the Wistar ataxic rat

The neuropathologic findings of the Wistar ataxic rat brain were reported after making serial sections of the brain and studying the cerebellum with an electron microscope. Twenty‐five adult Wistar rats from a mutant strain were used: 14 were ataxic and 11 were normal. In the brains of the Wistar ataxic rats, neuropathologic abnormalities were present only in the Purkinje cells. The possibility of a new model animal with autosomal recessive cerebellar ataxia is discussed.

Apoptotic nuclear degeneration in Marinesco-Sjögren syndrome.

In 12 patients with the clinical characteristics of Marinesco-Sjögren syndrome including an autosomal recessive inheritance, congenital cataracts, mental retardation, cerebellar ataxia and progressive muscle weakness, the most common pathological finding was rimmed vacuole formation comprising from 0.1% to 10% of fibers in their muscle biopsy samples. The nuclear changes varied from condensed chromatin granules to vacuolation with amorphous inclusions which were predominantly seen in younger patients with prominent rimmed vacuoles, suggesting a close relationship between nuclear change and rimmed vacuole formation. From the severe destructive changes in nuclei, we speculated that the nuclear changes in Marinesco-Sjögren syndrome play a primary role in muscle degeneration resulting in myofibrillar disorganization and rimmed vacuole formation. In 2 patients, the TUNEL method demonstrated scattered myonuclei with fragmented DNA, but "ladder formation" was not found, probably because of the small numbers of nuclei with fragmented DNA. Nuclear degeneration with focal myofibrillar degeneration seen in these muscle samples suggests that the apoptotic process may occur in muscle disorders, especially in diseases with rimmed vacuole formation.

1-36-05 Autosomal recessive cerebellar ataxia with slow eye movements: Review of 8 families

1-36-05 Autosomal recessive cerebellar ataxia with slow eye movements: Review of 8 families

Neuropathologic abnormalities of the brain in the Wistar ataxic rat

The neuropathologic findings of the Wistar ataxic rat brain were reported after making serial sections of the brain and studying the cerebellum with an electron microscope. Twenty-five adult Wistar rats from a mutant strain were used: 14 were ataxic and 11 were normal. In the brains of the Wistar ataxic rats, neuropathologic abnormalities were present only in the Purkinje cells. The possibility of a new model animal with autosomal recessive cerebellar ataxia is discussed.

HEREDITARY ATAXIAS AND PARAPLEGIAS IN CANTABRIA, SPAIN

A clinical, genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day, 103 patients were alive, giving a prevalence of 20.2 cases per 100,000. There were 24 patients (18 families) with Friedreich's ataxia (FA), 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA, 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA), 11 with 'idiopathic' LOCA, 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP), and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients, 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family, and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition, there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance, cerebellar ataxia, retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2, and autosomal recessive in 2 families.