Hereditary dystonia-parkinsonism syndrome of juvenile onset

We studied a family with an extrapyramidal disorder characterized by childhood onset of lower-limb and axial dystonia, followed by parkinsonism. Dramatic response to levodopa therapy and minimal progression in adult life was seen. The family included five generations of affected members of both sexes in an autosomal dominant pattern.     

Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder linked to chromosome 19q13 that is characterized by sudden onset of primarily bulbar and upper limb dystonia with parkinsonism. METHODS: The authors evaluated 12 individuals from three generations of an Irish family and obtained detailed medical records on a deceased member. The authors describe the clinical, psychiatric, and genetic features of the affected individuals. RESULTS: Five of eight affected members developed sudden-onset (several hours to days) dystonia with postural instability. Four of the five also had bulbar symptoms. Two have stable focal or segmental limb dystonia. One has intermittent hemidystonia with dysarthria that comes on abruptly in times of stress or anxiety. Three had a history of profound difficulty socializing, and at presentation two developed depression. Three patients had a trial of dopamine agonists without benefit. Genetic analysis suggests linkage to chromosome 19 with lod score of 2.1 at zero recombination. CONCLUSION: This is the third reported family with chromosome 19q13 rapid-onset dystonia-parkinsonism. Psychiatric morbidity appeared common in affected members of this family and may be part of the RDP phenotype.     

New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism

BackgroundA woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.MethodsThe mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.ResultsIn this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.ConclusionsThe phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.     

Autosomal dominant partial epilepsy with auditory features: description of a new family

PURPOSE: To report the clinical and genetic study of a new family with autosomal dominant partial epilepsy with auditory features (ADPEAF). METHODS: All the living affected members underwent a full clinical, neurophysiological, and magnetic resonance imaging (MRI) study. Genetic analysis was performed by typing their DNA with seven microsatellite markers previously found to cosegregate with ADPEAF on chromosome 10q24. RESULTS: The three living affected members had a childhood onset of rare and drug-responsive tonic-clonic seizures constantly preceded by a humming sensation. Routine and sleep electroencephalograms revealed rare and inconstant focal abnormalities over both temporal regions. MRI detected atrophy with increased T2 signal in the subcortical lateral portion of the right temporal lobe in one case. Analysis of 10q24 polymorphic alleles showed the same haplotype in all three affected members but different alleles in unaffected individuals. CONCLUSIONS: ADPEAF is a distinct condition with homogeneous clinical features. Genetic findings are consistent with linkage of ADPEAF to chromosome 10q24.     

Rapid-onset dystonia-parkinsonism: a fourth family consistent with linkage to chromosome 19q13.

Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement disorder characterized by abrupt onset of slow, dystonic movements and prominent bulbar features. Three families and 1 isolated case have been described in the literature, and linkage to markers on chromosome 19q13 have been reported. Here, we describe the clinical features in a fourth family (the second in Europe) with 4 affected members, suggesting that RDP may be misdiagnosed for years and/or may mimic other dystonic/parkinsonian syndromes. By using haplotype analysis, we show that the family is consistent with linkage to markers on chromosome 19q13.     

Genetic approach to heterogeneity in psychoses: relationship of a family history of mania or depression to course in bipolar illness

A specific family history or genetic background may be used to distinguish valid subgroups in patients who show similar symptoms. Also, a familial background may predict differences in other characteristics, i.e. course of illness, response to treatment or biological characteristics. Two hundred and fifty-one bipolar patients were separated according to their family history, 20 with a family history of mania with or without depression, 86 with a family history of depression only, and 145 with a family history of neither mania nor depression. The group that had a family history of mania was notable in that it showed more episodes of affective illness and was more likely to be readmitted to hospital. This difference in course suggests a familial association with multiple episodes and mania. In other respects than in course of illness, the groups separated by family history were similar.     

Phenotypic heterogeneity within a new family with the MAPT p301s mutation

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17. Clinical variability is seen not only among families with different mutations, but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia and parkinsonism family. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and it preceded dementia. Three autopsied cases shared involvement predominantly in the frontal and temporal lobes and also in the subcortical nuclei, including substantia nigra, globus pallidus, and subthalamic nucleus, that microscopically consisted of neuronal loss, microvacuolation, and astrocytic fibrosis. Immunohistochemistry demonstrated neuropil threads, ballooned cells, and glial fibrillary tangles. Sequencing analysis of the MAPT gene showed an alteration in one allele, resulting in a P301S substitution. These findings suggest that the MAPT P301S mutation can cause pathologically subcortical-predominant, neuropil thread-rich, tau-containing lesions, which could result in consistent parkinsonism. Our study confirms the notion that the phenotype observed in affected individuals from P301S MAPT mutation families is heterogeneous and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations.     

Epilepsy associated with hypocalcemia: description of a family.

The unusual occurrence of epilepsy and hypocalcemia in the same family is described. Epilepsy was present in three siblings (convulsive generalized in two females and partial in one male). All six family members had calcium ion, plasmatic phosphorus, plasmatic and erythrocytic potassium, urine calcium and phosphate concentration below the normal levels. Altered values of calcium-induced potassium membrane permeability were found in three subjects (two of them also affected by epilepsy). The assumption that alterations of membrane structure or function play an essential role in determining familial epilepsy and that the normal "set point" for calcium is genetically determined in familial hypocalcemia could explain the concomitance of both pathologies to some extent.     

R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family

Background:  PLA2G6 mutations are known to be responsible for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). In addition, novel mutations in PLA2G6 have recently been associated with dystonia-parkinsonism in two unrelated consanguineous families.
Methods:  Direct sequencing analysis of the PLA2G6 gene.
Results:  Here, we report the segregation of R632W with disease in an Iranian consanguineous dystonia-parkinsonism pedigree. The identical mutation was previously observed in a patient affected with NBIA.
Conclusion:  We conclude that different and even identical PLA2G6 mutations may cause neurodegenerative diseases with heterogeneous clinical manifestations, including INAD, NBIA and dystonia-parkinsonism.     

Myotilinopathy in a family with late onset myopathy

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.     

Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1

Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.     

Machado-Joseph disease: description of 5 members of a family]

The authors report the clinical and laboratorial findings of 5 affected members (all males) of a family with Machado-Joseph disease. The mode a inheritance was autosomal dominant. The mean onset age was 38 years (range 30-50 years). The clinical picture was pleomorphic and included cerebellar ataxia, external ophthalmoplegia with bulging eyes, extrapyramidal/pyramidal syndromes, amyotrophy with fasciculations and peripheral neuropathy, in variable degrees of severity. In one patient parkinsonian rigidity was greatly improved with the use of trihexaphenidyl and L-dopa. CT scan examinations disclosed a variable degree of cerebellar atrophy, with mild cerebral atrophy in one patient. Brainstem evoked potentials were normal in two patients. EMG showed denervation in three patients. Muscle biopsy (gastrocnemium) with histochemical studies revealed chronic muscle denervation in four cases. Sural nerve biopsy with conventional pathological study was normal in four cases. This family was living in Florianopolis, Santa Catarina, where there is a great number of Portuguese descendants from the Azores Islands. The worldwide presence of the disease seems to result from the genic diffusion of the disease with the Portuguese emigration during the Great Navigations Era and with some later emigratory settlement.     

Variable onset of metachromatic leukodystrophy in a Vietnamese family

We report two siblings with metachromatic leukodystrophy, one who presented at 7 years of age (juvenile onset) and his sister who presented at 22 years of age (adult onset). They are compound heterozygotes for two novel mutations in the arylsufatase A gene (ARSA). The responsible mutations in this Vietnamese family consist of a missense mutation with 5% enzyme activity (R143G) and a nonsense mutation (W318ter), from which no enzyme activity would be expected. These mutations in the ARSA gene have not been previously reported and may be useful when diagnosing metachromatic leukodystrophy in other affected Vietnamese individuals. The variability in presentation suggests that the genotype alone is not sufficient to determine the onset and course of the disease and modifying genetic and perhaps nongenetic factors likely contribute.     

Genetic heterogeneity in Duchenne dystrophy

We evaluated 173 patients in the Clinical Investigation of Duchenne Dystrophy study to determine if patients from the same kindred were more alike clinically than patients within the study population as a whole. A high intrafamilial correlation was noted for age-adjusted muscle strength scores. While noninherited factors could, in part, explain the results, it seems likely that genetic heterogeneity may contribute to the observed similarity within Duchenne dystrophy kindreds.