A family with autosomal dominant leukodystrophy linked to 5q23.2–q23.3 without lamin B1 mutations

Background and purpose: Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult‐onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. Methods: We carried out a genome‐wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real‐time PCR, multiplex ligation‐dependent probe amplification and Southern blot. Results: We mapped the variant ADLD locus to 5q23.2–q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy‐number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. Conclusions: This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.     

Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.     

Adult-onset autosomal dominant leukodystrophy and neuronal intranuclear inclusion disease: lessons from two new Chinese families

Neurological Sciences - Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare genetic leukoencephalopathy caused by duplication of the lamin B1 gene (LMNB1) or LMNB1 upstream deletions....     

Adult-onset autosomal dominant myoclonic epilepsy: report of a family with an overlooked epileptic syndrome.

OBJECTIVE: Myoclonic epilepsy is a common epileptic syndrome with high genetic contribution. We described a pedigree in which 10 individuals presented with a non-progressive, adult-onset myoclonic epilepsy. MATERIALS AND METHODS: The pedigree was constructed and analyzed. Six affected members were studied with clinical grounds, mental status, neurophysiology, video-electroencephalographic (EEG), brain magnetic resonance imaging (MRI) and mutational analysis of GABRA1 (GABRA1A, which endoces the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A). Clinical and EEG data were collected from six unaffected members. RESULTS: Autosomal dominant hereditary was shown. The age of seizure onset was approximately 40. All the individuals had myoclonic seizures and a normal cognitive level. Bilateral symmetric jerks of the shoulders, arms or legs featured the myoclonic seizure. Ictally, the consciousness was not affected. The ictal EEG demonstrated bilateral spikes-and-waves. The occurrence of myoclonic seizures was not associated with sleepiness. Rare generalized tonic-clonic seizures occurred in two individuals. No absence or accompanying involuntary movements were observed. A lower dose of valproic acid (200-500 mg/D) (clonazepam 0.5 mg/D in a patient) was required to stop the myoclonic seizures. CONCLUSIONS: The clinical features of late adult-onset autosomal dominant myoclonic epilepsy are similar to juvenile myoclonic epilepsy (JME), which is a common generalized epileptic syndrome with a significant hereditary component. But the age of onset, rare association of other seizure patterns, and non-relation of seizure onset to sleepiness suggest that this may be a distinct familial epileptic syndrome different from recognized familial myoclonic epilepsies.     

Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery-Dreifuss muscular dystrophy

Mutations in the LMNA gene encoding the nuclear envelope protein, lamins A and C, have been associated with at least nine distinct disorders now called laminopathies, including Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth type 2 disease. We identified a novel mutation in the 5' region of the LMNA gene -3del15, resulting in the loss of 15 nucleotides from -3 to +12, including the translation ATG initiator codon. The mutation segregates in a previously described family with a clinical phenotype that shared features of both Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth type 2. Thus, the mutation with this unique phenotypical expression represents the first example for a link between the neurogenic and myogenic phenotypes and extends the clinical variability of laminopathies.     

The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis

BACKGROUND: Distal myopathies (MPDs) are genetically heterogeneous. Genetic causes within this subgroup of muscle disorders remain largely unknown. An MPD linked to chromosome 14q11-q13 (MPD1) is rare, and to our knowledge, only one family with definitive linkage has been described. OBJECTIVE: To describe the results of clinical and genetic analysis of the second kindred with MPD1. PATIENTS AND METHODS: We have identified a family with an MPD segregating in an autosomal dominant fashion. We tested linkage to previously identified genetic loci on chromosomes 2p, 2q, and 14q. The coding sequence of PABP2 (the polyadenylate-binding protein 2 gene) was analyzed. RESULTS: Every affected individual had selective weakness of foot extensors, with the average age of symptom onset at 20 years. Some patients also had proximal weakness, but none had signs of finger or hand extensor muscle involvement, even in advanced stages of the disease. Two typically affected individuals had signs of idiopathic dilated cardiomyopathy. Genetic analysis detected a tight linkage to chromosome 14q11-q13. Recombination at the telomeric end of the 14q11-q13 locus was found in an unaffected individual who was not considered to be at risk, potentially reducing the locus interval by 2 centimorgans. No mutations in the PABP2 gene were identified. CONCLUSIONS: To our knowledge, our described family is only the second known kindred with a chromosome 14-linked MPD in whom the linkage has been unequivocally established. We did not detect signs of involvement of hand or finger extensors and neck muscles, seen in the original family with MPD1. The degree and frequency of proximal weakness seem to be more prominent than in other patients with MPD1. Haplotype analysis suggests that the gene is located between polymorphic microsatellite markers D14S283 and D14S1034 on chromosome 14q11-q13. The presence of cardiomyopathy in some affected individuals may help in the identification of candidate genes.     

Long-term follow-up of a patient with autosomal dominant lower extremity-predominant spinal muscular atrophy-2 due to a BICD2 variant

IntroductionBicaudal D homolog 2 (BICD2) is a causative gene of autosomal-dominant lower extremity-predominant spinal muscular atrophy-2 (SMA-LED2). The severity of SMA-LED2 varies widely, ranging from cases in which patients are able to walk to cases in which severe joint contractures lead to respiratory failure. In this study, we report the long-term course of a case of SMA-LED2 in comparison with previous reports.Case reportThe patient was a 19-year-old woman. She had knee and hip dislocations with contractures, femoral fracture, and talipes calcaneovalgus since birth, and was diagnosed with arthrogryposis multiplex congenita. Intense respiratory support was not needed during the neonatal period. She had aspiration pneumonia repeatedly, necessitating NICU admission until 8 months of age. She achieved head control at 9 months of age and was able to sit at 2 years of age; however, she could not walk. Tube feeding was required until 3 years of age. At present, she can eat orally, move around with a wheelchair, and write words by herself. She needs non-invasive positive pressure ventilation during sleep because of a restrictive respiratory disorder during adolescence. Exome analysis identified a de novo heterozygous missense variant (c.2320G>A; p.Glu774Lys) in BICD2.ConclusionPatients with SMA-LED2 may have a relatively better prognosis in terms of social activities in comparison with the dysfunction in the neonatal period. Moreover, it is important to periodically evaluate respiratory function in patients with SMA-LED2 because respiratory dysfunction may occur during adolescence.     

A 17th-century founder gives rise to a large north American pedigree of autosomal dominant spinocerebellar ataxia not linked to the SCA1 locus on chromosome 6.

There have been three reports since 1969 of members of a "W" family with autosomal dominant spinocerebellar ataxia (SCA), and various conclusions have been drawn about the nosology. This pedigree has been traced back over 300 years through 11 generations. Although phenotypically similar to the disorder in the Schut-Swier, Nino, and other kindreds, the disorder in the W family is not linked to the SCA1 locus on chromosome 6, as reported in those hereditary ataxia pedigrees. The W family represents the largest such North American kindred yet reported. We examined 33 family members of a distantly related branch of the W family, determined the cumulative age of onset, and projected the number of present-day gene carriers. Two cases illustrate the spectrum of symptoms among family members. Age of onset and presenting symptom, however, seem to correlate both in our patients and in those previously reported. Between 2,000 and 5,000 individuals are estimated to be at risk of developing the disorder within this pedigree alone. The pedigree reported here will be valuable in the identification and cloning of a gene for hereditary ataxia, designated "SCA2" at the Eleventh International Workshop on Human Gene Mapping.     

Nuclear changes in skeletal muscle extend to satellite cells in autosomal dominant Emery-Dreifuss muscular dystrophy/limb-girdle muscular dystrophy 1B

Autosomal forms of Emery-Dreifuss muscular dystrophy (AD-/AR-EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are caused by mutations in the gene encoding A-type lamins (LMNA). A-type lamins are major components of nuclear lamina and known to have important roles in maintaining nuclear integrity. LMNA mutations are also suggested to cause reduced myogenic differentiation potentials, implying that satellite cell nuclei in AD-EDMD/LGMD1B are likewise affected. We examined nuclear changes of skeletal muscles including satellite cells from four patients with AD-EDMD/LGMD1B by light and electron microscopy. We found that 92.5 ± 5.0% of myonuclei had structural abnormalities, including shape irregularity and/or chromatin disorganization, and the presence of peri-/intranuclear vacuoles. Chromatin changes were also observed in 50% of the satellite cell nuclei. Increased number of Pax7-positive nuclei, but fewer number of MyoD-positive nuclei were seen on immunohistochemical analyses, suggesting functional alteration of satellite cells in addition to the nuclear morphological changes in AD-EDMD/LGMD1B.     

Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness?

BACKGROUND: Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. METHODS: Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). RESULTS: Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD (n = 12) than for the non-PDD (n = 27) subgroup (-19.5 +/- 11.3 mL/year vs. -9.6 +/- 15.3 mL/year; p =.05). None of eight candidate genes for autism were associated with COS or COS-PDD. CONCLUSIONS: Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.     

A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci

We describe a novel autosomal dominant myopathy presenting in mid-adult life with tibialis anterior weakness. We carried out a detailed clinical assessment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an autopsy study on one case. The second generation of affected individuals presented at an earlier age, and the disease progressed more rapidly than in the first generation. Lung function tests revealed progressive global respiratory muscle weakness detectable from the time of presentation, with preferential diaphragmatic involvement in some cases. Hip girdle and shoulder girdle weakness appeared later in the disease course. We observed a striking correlation between the clinical and pathological features. Clinically unaffected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affected muscles, and fat and fibrous connective tissue replaced muscle fibers in the severely involved muscles. The inclusions were Congophilic and reacted with antibodies to desmin, beta-amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myopathies, confirming that the disorder in this family is both genetically and phenotypically distinct.     

A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci.

Sensory loss and ulcero-mutilating features have been observed in hereditary sensory neuropathy type I and in hereditary motor and sensory neuropathy type IIB, also referred as Charcot-Marie-Tooth disease type 2B. To date two loci associated with ulcero-mutilating neuropathy have been described: CMT2B at 3q13-q22 and HSN I at 9q22.1-q22.3. We performed linkage analysis with chromosomal markers representing the hereditary sensory neuropathy type I and Charcot-Marie-Tooth disease type 2B loci on an Italian family with a severe distal sensory loss leading to an ulcero-mutilating peripheral neuropathy. Negative likelihood-of-odds scores excluded any evidence of linkage to both chromosome 3q13 and chromosome 9q22 markers, confirming the genetic heterogeneity of this clinical entity and the presence of a third locus responsible for ulcero-mutilating neuropathies.     

Variable expressivity of a novel mutation in the SCN1A gene leading to an autosomal dominant seizure disorder

Mutations in the SCN1A gene can cause a variety of dominantly inherited epilepsy syndromes. Severe phenotypes usually result from loss of function mutations, whereas missense mutations cause a milder phenotype by altering the sodium channel activity. We report on a novel missense variant (p.Val1379Leu) in the SCN1A gene segregating in an autosomal dominant pattern in a family exhibiting a variable epilepsy phenotype ranging from generalized epilepsy with febrile seizures during infancy to a well controlled seizure disorder in adulthood. This report supports the importance of SCN1A mutation analysis in families in which seizure disorders segregate in an autosomal dominant fashion.     

Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27

OBJECTIVE: To describe clinical and neuropathologic studies and linkage analysis on two sisters with a severe form of leukodystrophy. METHODS: A detailed study was performed on the second sister. Genotyping markers for chromosome 3, including eight additional markers surrounding the vanishing white matter (VWM) locus, were used. RESULTS: During the first year of life, two sisters developed a severe neurologic condition after an intercurrent infection. It was accompanied by irritability and stupor with rapid loss of their motor abilities. Results of extensive metabolic studies were negative. Brain MRI showed severe and diffuse abnormalities of the encephalic white matter. Neuropathologic examination showed a severe lack of myelin with diffuse vacuolating white matter lesions in the brain, associated with an increased density of oligodendrocytes and a reduced number of astrocytes on morphometric analysis. In sharp contrast, the spinal cord white matter was preserved. The affected sibpairs shared a common haplotype for a broad region in chromosome 3. They were homozygous between markers D3S1565 and D3S3669, including the VWM locus. CONCLUSIONS: This condition is an unusual variant of childhood ataxia with diffuse central hypomyelination (CACH)/VWM, with characteristic shrinking and perivascular clustering of astrocytes. Haplotype analysis suggests that this variant is allelic to the VWM locus located on chromosome 3q27.