Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum

Two brothers are reported with early onset progressive cerebellar ataxia, dystonia, spasticity, and intellectual decline. • Neuroradiology showed cerebellar atrophy and features compatible with iron deposition in the putamen (including the “eye of the tiger sign”) and substantia nigra. • Diagnosis was compatible with pantothenate kinase associated neuropathy resulting from pantothenate kinase 2 mutation (PKAN due to PANK2) but linkage to PNAK2 was eliminated suggesting Karak syndrome to be a novel disorder. • The “eye of the tiger” sign has previously only been reported to occur in PKAN due to PKAN

Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36

Kufor-Rakeb syndrome is an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration. The onset is in the teenage years with clinical features of Parkinson’s disease plus spasticity, supranuclear upgaze paresis, and dementia. Brain scans show atrophy of the globus pallidus and pyramids and, later, widespread cerebral atrophy. We report linkage in Kufor- Rakeb syndrome to a 9 cM region of chromosome 1p36 delineated by the markers D1S436 and D1S2843, with a maximum multipoint lod score of 3.6. (J Med Genet 2001;38:680–682

Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum

We report a Jordanian Arab family where two sibsdeveloped the classical clinical and radiological fea-tures of pantothenate kinase associated neurode-generation (PKAN, formerly known as Hallervorden-Spatz disease) but in addition had an early onset cerebellar ataxia.1 2 Using polymorphic microsatellite markers we have shown that this family is not linked to the pantothenate kinase gene (PANK2) on chromosome 20.2 We hypothesise that the disorder, Karak syndrome, is novel and a member of the growing family of neurological diseases involving excess cerebral iron accumulation, for example, PKAN, neuroferritin-opathy, aceruloplasminaemia, and Friedreich’s ataxia.2–6 CLINICAL STUDIES Both affected members (fig 1, IV.1 and IV.2) were the product of a normal pregnancy and birth and had normal develop-mental milestones and progress at school until disease onset at the age of 6 years. They developed an ataxic gait that wa

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene

Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. Methods: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon 723delC and epsilon 760ins8), one is a missense mutation in the signal peptide region (epsilon V-13D), one is a missense mutation in the N-terminal extracellular domain (epsilon T51P), and one is a splice donor site mutation in intron 10 (epsilon IVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries

Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation

BACKGROUND: Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. METHODS: We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. RESULTS: A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. CONCLUSION: In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A(2), in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis

PLA2G6, encoding a phospholipase A(2), is mutated in neurodegenerative disorders with high brain iron

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis