An unusual form of spinal muscular atrophy with mental retardation occurring in an inbred population.

Three sibs are described suffering from hereditary non-progressive spinal muscular atrophy with non-progressive mental retardation. One of them had in addition signs of pyramidal tract involvement. Muscular weakness was more pronounced proximally than distally and the neck muscles were severely involved. Th.ey all had small skulls and several associated congenital malformations were observed including syndactyly of the left hand in 1 patient. The patients belong to a small inbred community in the Netherlands. Erythropoietic protoporphyria was also present in the family but segregated independently. This combination of "congenital" mental retardation with "congenital" non-progressive spinal muscular atrophy is believed to represent a new syndrome, caused by a rare recessive gene.     

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.     

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.     

A case of congenital non-progressive cerebellar ataxia with pigmentary retinal degeneration, fiber type disproportion and hypercreatine kinasemia]

We report a 20-year-old female who presented with congenital non-progressive cerebellar ataxia, pigmentary retinal degeneration, fiber type disproportion, hypercreatine kinasemia and mental retardation. No family history of neuromuscular disorders was found. There was consanguinity between the grandfather and grandmother. Pregnancy and delivery were uneventful. Although neck control was obtained at three months old, she could walk at 23 months old. She had a tendency to tumble. Her mentality was retarded. At 12-years-old, she was diagnosed as having pigmentary retinal degeneration. When she visited to our hospital at 20-year-old, she had slight scoliosis. Neurological examination disclosed mental retardation, pigmentary retinal degeneration, gaze evoked nystagmus on horizontal gaze and proximal dominant muscle weakness. Tandem gait was unsteady. Deep tendon reflexes were slightly hyperactive in all four extremities. The serum creatine kinase was elevated to 2346U/l. Muscle biopsy revealed type I. fiber atrophy and predominance. This case is therefore considered to be cogenital non-progressive cerebellar ataxia presenting with fiber type disproportion, pigmentary retinal degeneration and hypercreatine kinasemia.     

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.     

Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation

We present here 5 patients with hereditary cerebellar ataxia with peripheral neuropathy and mental retardation as determined by clinical, pathological, and molecular studies. The most characteristic features of this disorder, in contrast to Friedreich's ataxia, were early onset of ataxic gait, mental retardation, and a marked atrophy of the cerebellum. Sural nerve biopsy showed a reduction of myelinated fibers. The expansion of a GAA triplet repeat within the first intron of the frataxin gene, which causes Friedreich's ataxia, was not identified in any of the patients. Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation represents a specific clinical entity that so far has only been described in Japan.     

Spastic paraplegia, ataxia, mental retardation (SPAR): a novel genetic disorder

OBJECTIVE: To describe a kindred with a dominantly inherited neurologic disorder manifested either as uncomplicated spastic paraplegia or ataxia, spastic paraplegia, and mental retardation. METHODS: Neurologic examinations and molecular genetic analysis (exclusion of known SCA and HSP genes and loci; and trinucleotide repeat expansion detection [RED]) were performed in six affected and four unaffected subjects in this family. MRI, electromyography (EMG), and nerve conduction studies were performed in three affected subjects. RESULTS: The phenotype of this dominantly inherited syndrome varied in succeeding generations. Pure spastic paraplegia was present in the earliest generation; subsequent generations had ataxia and mental retardation. MRI showed marked atrophy of the spinal cord in all patients and cerebellar atrophy in those with ataxia. Laboratory analysis showed that the disorder was not caused by mutations in genes that cause SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, and SCA-12; not linked to other known loci for autosomal dominant ataxia (SCA-4, SCA-5, SCA-10, SCA-11, SCA-13, SCA-14, and SCA-16); and not linked to known loci for autosomal dominant hereditary spastic paraplegia (HSP) (SPG-3, SPG-4, SPG-6, SPG-8, SPG-9, SPG-10, SPG-12, and SPG-13) or autosomal recessive HSP SPG-7. Analysis of intergenerational differences in age at onset of symptoms suggests genetic anticipation. Using RED, the authors did not detect expanded CAG, CCT, TGG, or CGT repeats that segregate with the disease. CONCLUSIONS: The authors describe an unusual, dominantly inherited neurologic disorder in which the phenotype (pure spastic paraplegia or spastic ataxia with variable mental retardation) differed in subsequent generations. The molecular explanation for apparent genetic anticipation does not appear to involve trinucleotide repeat expansion.     

Marinesco-Sjgren综合征的临床及影像学特征

目的　研究 Marinesco- Sjogren综合征的临床及影像学特征。方法　报告 1例 2 8岁女性Marinesco- Sjogren综合征患者的临床、实验室和影像学资料。结果　本例患者除具有小脑性共济失调、白内障、体格及智能发育障碍外 ,还有慢性肾功能障碍、甲状旁腺及性腺功能减退。染色体核型分析为 46 ,XX,1q+,2 2 s+。头颅 CT显示双侧豆状核 (壳及苍白球 )条片状高密度影 ,境界清楚 ,小脑萎缩 ;头颅 MRI显示小脑蚓部、半球体积小 ,小脑脑沟增宽 ,侧脑室、三脑室、四脑室、脑池扩大 ,左颞叶脑回增大 ,胼胝体膝部略细小。结论　 Marinesco- Sjogren综合征具有体格及智能的发育障碍、先天性白内障、小脑性共济失调等临床特征。头颅 MRI检查有助于对 Marinesco- Sjogren综合征的早期诊断。     

Carbohydrate-deficient glycoprotein syndrome: clinical expression in adults with a new metabolic disease.

A new group of recessively inherited metabolic disorders affecting glycoprotein metabolism has been identified--the carbohydrate-deficient-glycoprotein (CDG) syndromes. Here the course and clinical expression of CDG syndrome type I in 13 patients who have passed the age of 15 years are described. All presented with early onset psychomotor retardation, in most cases combined with slight facial dysmorphic features, some degree of hepatic dysfunction, and in one case, pericardial effusion. About half of the patients had subcutaneous lipodystrophy and comatose or stroke-like episodes during childhood. After the age of 15 the disease was mainly characterised by neurological symptoms consisting of non-progressive ataxia associated with cerebellar hypoplasia, stable mental retardation, variable peripheral neuropathy, and strabismus. One third of the patients had generalised seizures, usually sporadic, and all had retinal pigmentary degeneration. In all cases there was more or less pronounced thoracic deformity and no female had passed puberty. Also, the oldest female showed premature aging. Severe internal organ symptoms, which are common in pediatric patients, were absent. All patients had highly raised serum concentrations of the biochemical marker carbohydrate-deficient transferrin, which can be used to verify the diagnosis. It is concluded that after childhood, CDG syndrome type I is a largely non-progressive disease compatible with a socially functioning but dependent lifestyle.     

Progression of tremor and ataxia in male carriers of the FMR1 premutation.

Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late-onset movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family-based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at approximately 60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.     

Autosomal recessive congenital cerebellar atrophy A clinical and neuropsychological study

Congenital cerebellar atrophy associated with a non-progressive cerebellar syndrome and mild cognitive retardation is described in seven cases, four of them familial. Their occurrence is consistent with an autosomal recessive inheritance. Clinical and neuroimaging data seem to exclude supratentorial changes. Even though it is not possible to definitely rule out a possible role of the forebrain in determining the mental defect, the neuropsychological study supplies arguments stressing the relationship between cerebellar defect and cognitive development.     

Non-progressive leukoencephalopathy with bilateral anterior temporal cysts: a case report and review of the literature

A newly described disease is characterized by anterior bilateral temporal lobe cysts associated with multilobar leukoencephalopathy and a non-progressive clinical course. We report a patient with bilateral anterior temporal lobe cystic changes associated with a non-progressive neurological disorder, microcephaly, spasticity, mental retardation, and sensorineural deafness. From the literature, 12 other patients have shown a similar phenotype. The common neuroradiological findings in these patients have been bilateral anterior temporal lobe cystic changes and non-progressive leukoencephalopathy. By contrast, variability in the clinical phenotype has been observed, ranging from severe neuromotor handicap with mental retardation and microcephaly to spasticity in the lower limbs associated with normal cognitive function. The pathological basis of the defect remains to be defined.     

A case of Friedreich's ataxia having no abnormal gene

We report here a 25-year-old girl with Friedreich's ataxia (FA) who showed slowly progressive ataxia, deep sensory disturbance and loss of large myelinated fiber in the sural nerve. There was no evidence of cerebellar atrophy or abnormal values of vitamin E, albumin, CK, and gamma-globulin in the serum. Except for mild mental retardation, her clinical and laboratory findings were consistent with those of FA. However, she had no abnormal GAA trinucleotide repeat expansion on chromosome 9q13, unlike typical FA patients in Europe. Her cardiac muscle is not involved instead of 20 years have passed since her ataxia developed. She is considered to belong to a specific type of FA which lacks cardiac muscle involvement and abnormal gene encoding frataxin.     

Beta-mannosidosis: a new cause of spinocerebellar ataxia

Beta-mannosidosis (OMIM 248510) is an inborn lysosomal storage disorder caused by deficiency of beta-mannosidase activity. This enzyme is encoded by a single gene (MANBA), located on chromosome 4q22-25. This autosomal recessive disorder is characterized by a wide range of symptoms including mental retardation, behavioural problems, hearing loss, recurrent respiratory infections, angiokeratoma, facial dysmorphism, skeletal deformation, seizures, hypotonia, demyelinating polyneuropathy, and hepatosplenomegaly. The age of symptom onset is variable. We describe a 14-year clinical follow-up of a patient with beta-mannosidase deficiency with symptoms of mental retardation, progressive spasticity and cerebellar ataxia, a clinical spectrum that so far has never been reported in beta-mannosidosis. A novel mutation in the MANBA gene was found in our patient. Evoked potentials were in favour of a demyelinating pathology of the central nervous system. Serial MRI showed generalized cortical and subcortical atrophy in the absence of white matter changes suggesting an additional axonal pathophysiological component.     

Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum

Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22 year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.     

Autosomal recessive cerebellar hypoplasia in the Hutterite population

Cerebellar hypoplasia is a rare malformation caused by a variety of etiologies. It usually manifests clinically as non-progressive cerebellar ataxia with or without mental retardation. We further characterize a syndrome of autosomal recessive cerebellar hypoplasia in the Hutterite population, referred to as dysequilibrium syndrome (DES). We reviewed 12 patients (eight females, four males; age range 4 to 33 y) with this syndrome. Patients were examined and underwent a standard set of investigations to characterize better the clinical features, natural history, and neuroimaging of this syndrome. DES is an autosomal recessive disorder with distinct clinical features including global developmental delay, late ambulation (after age 6 y), truncal ataxia, and a static clinical course. Neuroimaging is characterized by hypoplasia of the inferior portion of the cerebellar hemispheres and vermis, and mild simplification of cortical gyri.     

Autopsy case of acute encephalopathy linked to familial hemiplegic migraine with cerebellar atrophy and mental retardation

A 19‐year‐old female patient, who had exhibited esotropia, mild cerebellar ataxia, mild mental retardation, and cerebellar atrophy on magnetic resonance images at the age of 15, developed signs of acute encephalopathy, and thereafter died of disseminated intravascular coagulation on the day of her admission. Both her mother and sister suffered from attacks of hemiplegic migraine, mild mental retardation, and cerebellar ataxia. Neuropathological examinations revealed acute changes in the widespread cerebral cortex, chronic degenerative changes in the anterior lobe of the cerebellar vermis, axonal spheroids in the Goll's nucleus, pseudo‐calcinosis in the globus pallidus, and glial bundles in the cranial nerves. The most fascinating features were changes of Purkinje cells, such as cactuses (asteroid bodies, dendritic expansions), somatic sprouts, and torpedoes. These changes may be characteristic of familial hemiplegic migraine with cerebellar atrophy, as well as the other metabolic diseases, such as Menkes’ kinky hair disease, infantile (Tay–Sachs type) amaurotic idiocy, organic mercury intoxication, and mitochondrial encephalopathy, of which cases often exhibit such pathological changes of Purkinje cells. Therefore, familial hemiplegic migraine may share some metabolic abnormalities with the diseases mentioned above.     

Stepwise developmental regression associated with novel CACNA1A mutation

Mutations in CACNA1A were previously described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. We report on an 11-year-old girl with episodes of seizures, ataxia, headache, a decreased level of consciousness, and motor regression, with a background of mental retardation and mild cerebellar atrophy. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously.     

Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome

OBJECTIVE: We evaluated patients with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with a CGG repeat expansion in the premutation range in the fragile X mental retardation 1 (FMR1) gene. METHODS: Neurological, psychiatric and neuropsychological evaluations were performed on 15 male patients with FXTAS. RESULTS: Seven cases were diagnosed with dementia, and seven others were diagnosed with mood and/or anxiety disorders. Twelve subjects demonstrated deficits on neuropsychological testing. CONCLUSIONS: Physicians assessing dementia patients are urged to consider this newly described syndrome, especially in patients with dementia associated with a movement disorder and in those with a family history of mental retardation. If FXTAS is a possible diagnosis, physicians may carry out FMR1 DNA testing; patients who test positive on DNA testing should undergo magnetic resonance imaging, be referred to neurology and receive genetic counseling.     

FMR1 gray‐zone alleles: Association with Parkinson's disease in women?

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG‐repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray‐zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2–8.7). Gray‐zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray‐zone alleles may be associated with Parkinson's disease in women. © 2011 Movement Disorder Society