Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus

Background: Most patients with pure nonprogressive congenital cerebellar ataxia have a sporadic form of unknown heredity and etiology. Several small families have been reported with a dominantly inherited nonprogressive congenital ataxia (NPCA). Methods: The authors ascertained and clinically characterized a four-generation pedigree segregating an autosomal dominant type of congenital nonprogressive cerebellar ataxia associated with cognitive impairment. Following the exclusion of several SCA localizations (SCA-1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 17, IOSCA, and DRPLA), a genome-wide linkage study was performed. Results: Examination of the family showed that all affected members had gait ataxia and cognitive disability with variable features of dysarthria, dysmetria, dysdiadochokinesia, nystagmus, dystonic movements, and cerebellar hypoplasia on imaging. Clinical signs of pyramidal tract dysfunction and sensory changes were absent. A genome-wide search in this family detected linkage to chromosome 3p with a maximum two-point lod score of 4.26 at D3S3630. This localization to the pter is distal to D3S1304, as defined by a recombination event. This overlaps with the SCA15 locus, with the critical overlapping region between the microsatellite markers, D3S1304 and D3S1620 (approximately 8 cM). Conclusion: Autosomal dominant congenital nonprogressive cerebellar ataxia with or without cerebellar hypoplasia overlaps with the SCA15 locus on chromosome 3pter.

[1]  G. Fenichel,et al.  Familial aplasia of the cerebellar vermis. Possible X-linked dominant inheritance. , 1989, Archives of neurology.

[2]  E. Bertini,et al.  X-linked congenital ataxia: a clinical and genetic study. , 2000, American journal of medical genetics.

[3]  R. Pfeiffer,et al.  Nosology of congenital non-progressive cerebellar ataxia. Report on six cases in three families. , 1974, Neuropadiatrie.

[4]  M. Baraitser,et al.  Dominantly inherited congenital cerebellar ataxia with atrophy of the vermis. , 1987, Pediatric neurology.

[5]  F. Rivier,et al.  Dominantly inherited hypoplasia of the vermis. , 1992, Neuropediatrics.

[6]  M. Steinlin Non-progressive congenital ataxias , 1998, Brain and Development.

[7]  M. Steinlin Non‐progressive congenital ataxia with or without cerebellar hypoplasia: a review of 34 subjects , 1998, Developmental medicine and child neurology.

[8]  R. Norman PRIMARY DEGENERATION OF THE GRANULAR LAYER OF THE CEREBELLUM: AN UNUSUAL FORM OF FAMILIAL CEREBELLAR ATROPHY OCCURRING IN EARLY LIFE , 1940 .

[9]  A. L. Leiner,et al.  Cognitive and language functions of the human cerebellum , 1993, Trends in Neurosciences.

[10]  E. Mercuri,et al.  Autosomal recessive congenital cerebellar atrophy A clinical and neuropsychological study , 1993, Brain and Development.

[11]  R. Anney,et al.  Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant , 2003, Neurobiology of Disease.

[12]  I. Kanazawa,et al.  Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus , 2004, Neurology.

[13]  B. Kendall,et al.  Ataxia, Developmental Delay and an Extensive Neuronal Migration Abnormality in 2 Siblings , 1990, Neuropediatrics.

[14]  A. Kriss,et al.  Autosomal recessive cerebellar hypoplasia. , 1993, Pediatric neurology.

[15]  A. Wichman,et al.  Autosomal recessive congenital cerebellar hypoplasia , 1985, Clinical genetics.

[16]  A. Kornberg,et al.  An Extended Phenotype of an Early-Onset Inherited Nonprogressive Cerebellar Ataxia Syndrome , 1991, Journal of child neurology.

[17]  J. R. Moore,et al.  Sex-linked recessive congenital ataxia. , 1987, Journal of neurology, neurosurgery, and psychiatry.

[18]  K. Gustavson,et al.  IDENTICAL SYNDROMES OF CEREBRAL PALSY IN THE SAME FAMILY , 1969, Acta paediatrica Scandinavica.

[19]  N. Tachi,et al.  Dominantly inherited early-onset non-progressive cerebellar ataxia syndrome , 1993, Brain and Development.

[20]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[21]  E. Boltshauser,et al.  Cognitive impairments in patients with congenital nonprogressive cerebellar ataxia , 1999, Neurology.

[22]  G. Lathrop,et al.  Easy calculations of lod scores and genetic risks on small computers. , 1984, American journal of human genetics.

[23]  S. Tsuji,et al.  X‐linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq , 1996, Annals of neurology.

[24]  H. Chugani,et al.  Infantile cerebellar atrophy , 1985, Annals of neurology.

[25]  I. Pascual-Castroviejo,et al.  Primary Degeneration of the Granular Layer of the Cerebellum. A Study of 14 Patients and Review of the Literature , 1994, Neuropediatrics.

[26]  K. Mathews,et al.  Autosomal Recessive Cerebellar Hypoplasia , 1989, Journal of child neurology.

[27]  B. Hagberg,et al.  188 Cases of Non-Progressive Ataxic Syndromes in Childhood – Aspects of aetiology and classification , 1974, Neuropadiatrie.

[28]  G. Jervis Early familial cerebellar degeneration; report of 3 cases in one family. , 1950, The Journal of nervous and mental disease.