H. Karasoy

DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability

Familial parkinsons disease is both clinically and genetically heterogeneous. By mapping the disease locus with a lod score of 5.13 to a < 3.5 Mbp region at 1p31.3 in a consanguineous family and subsequent exome sequencing analysis, we identified homozygous truncating mutation p.Q734X in DNAJC6. Four members of the family were afflicted with juvenile parkinsonism that presented with mental retardation, pyramidal signs and epilepsy, as well as varying degrees of a progressive neurological disease. Recently a splicing mutation in the same gene was reported in two brothers with juvenile parkinsonism that was not L-Dopa responsive and not accompanied by pyramidal signs or mental retardation. Also, an 80-kb deletion that included DNAJC6 sequences was identified in a boy reported as having obesity, epilepsy and mental retardation but not any signs of parkinsonism. The phenotype of our study family resembles both of those families, which among themselves do not share any clinical features. Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation. DNAJC6 encodes the neuronal co-chaperone auxilin. We found that its transcript is highly significantly more abundant in brain as compared to the non-neural tissues assayed.

Mutation spectrum in the large GTPase dynamin 2, and genotype–phenotype correlation in autosomal dominant centronuclear myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM‐related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice‐site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue‐specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33:949–959, 2012.

An integrated diagnosis strategy for congenital myopathies.

Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient’s access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.

Identification of a locus for an autosomal recessive hyaline body myopathy at chromosome 3p22.2 -p21.32

Hyaline body myopathy is a rare congenital disease with distinctive histopathological features. We performed homozygosity mapping in a family with two affected sibs and identified a gene locus with a maximum homozygosity region of 5.35 centi Morgans or 5.59 Megabases at chromosome 3p22.2-p21.32. The best candidate responsible for the disease is a novel gene that exhibits homology to the myosin heavy chain.

Proton MR spectroscopy in Rett syndrome

Seven patients (mean age 7.7yr) with Rett syndrome, a condition with progressive regression of psychomotor development are included in this study. Proton MR spectroscopy images were obtained with the multivoxel chemical-shift imaging mode (TR=1500ms, TE=40ms). Spectra from 224 voxels in the brain parenchyma were studied. N-acetyl aspartate (NAA), creatine (Cr), choline (Cho), and myoinositol (mI) peaks were quantitatively evaluated, and NAA/Cr, NAA/Cho, and Cho/Cr, mI/Cr ratios were calculated. Five age-matched normal cases were available as controls. In three patients with Rett syndrome spectroscopy findings were normal, and the metabolite ratios were similar to control cases. In the remaining four patients with the syndrome prominent decrease of the NAA peak was the main finding resulting in decreases in NAA/Cr (1.14+/-17), and NAA/Cho (1.08+/-27) ratios (p<0.0001). Cho/Cr ratios (0.93+/-26), and mI/Cr ratios (0.88+/-36) were normal compared to controls. There was no correlation between spectroscopic changes and clinical status of the patients. The findings suggested that not only reduced neuronal-dendritic arborizations but also decreased neuronal function could contribute to spectroscopy changes in Rett syndrome.

Atypical EEG findings in subacute sclerosing panencephalitis

OBJECTIVE To evaluate atypical electroencephalographic features in subacute sclerosing panencephalitis (SSPE) and to detect its relation to clinical features. METHODS Twenty-two patients aged 2-17 years (mean 9.4 years) with definite diagnosis of SSPE were studied. Their clinical data and EEG records were reviewed retrospectively. All EEG records were analysed for features of periodic complexes (PCs) in relation to age, age at onset, clinical stage and the rate of progression as well as duration of the disease. RESULTS Classical periodic complexes of SSPE were found in EEGs of 13 patients (group I). Atypical patterns were observed in EEGs of nine patients (group II). Two new atypical findings were identified: prolonged discharges which include sharp waves and slow waves for 4-7 s followed by suppression for 1-4s; and periodic complexes which consist of four or five sharp waves in every 2 s. We observed atypical EEG patterns were more frequently in Stage III, acute form, and the disease duration was longer than in the typical group. CONCLUSIONS Atypical EEG patterns in SSPE might be related to the progression of the disease, but this theory needs further longitudinal studies. SIGNIFICANCE We suggest atypical EEG patterns might be observed more frequently in patients with severe neurologic disability, more rapidly progressive disease and longer duration of disease.

Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: scapuloperoneal and respiratory weakness with dilated cardiomyopathy.

Myosin storage myopathy (MSM) is a protein aggregate myopathy caused by the accumulation of myosin in muscle fibres and results from MYH7 mutation. Although MYH7 mutation is also an established cause of variable cardiomyopathy with or without skeletal myopathy, cardiomyopathy with MSM is a rare combination. Here, we update the clinical findings in the two brothers that we previously reported as having recessively inherited MSM characterized by scapuloperoneal distribution of weakness and typical hyaline-like bodies in type 1 muscle fibres. One of the patients, weak from childhood but not severely symptomatic until 28 years of age, had an unusual combination of MSM, severe dilated cardiomyopathy, and respiratory impairment at the age of 44 years. We identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 in these patients as the second recessive MYH7 mutation reported to date.

Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1

We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.

Zuclopenthixol-induced neuroleptic malignant syndrome in an adolescent girl

We present the case of a 14-year-old female who had many characteristics of neuroleptic malignant syndrome (NMS) without pyrexia following a single depot injection of 200 mg of zuclopenthixol. The patient presented with a change in mental status that had progressed over the preceding 48 hours. Subsequently, she became increasingly agitated and confused, and developed diffuse muscular rigidity, mutism, tremor, tachycardia, diaphoresis, sialorrhea, and incontinence. Results of laboratory tests showed elevated CPK levels, leukocytosis, and a low serum iron level. Bromocriptine and diazepam were used as initial treatment of a probable NMS and provided significant improvement. During the next seven days, she clinically improved but continued to exhibit emotional lability, logorrhea, elevated mood, and increased psychomotor activity. Therefore, bromocriptine and diazepam were discontinued and lorazepam and lithium were administered as treatment of a bipolar disorder. Four weeks later, she was discharged in stable condition. The presentation of this case report suggests that the primary psychiatric diagnosis is important in antipsychotic usage in the pediatric population, and that young patients receiving neuroleptic treatment should be monitored for the early signs of NMS. Using the diagnostic criteria of a neuroleptic toxicity spectrum may result in greater clinical awareness and earlier recognition of NMS.

Sydenham chorea and Hashimoto thyroiditis: an unusual association.

Sydenham chorea is an immune-mediated neuropsychiatric disorder associated with group A β-hemolytic streptococci infection. The authors present a 12-year-old female patient with Sydenham chorea and Hashimoto thyroiditis. Although Hashimoto thyroiditis has been associated with other autoimmune disorders, the association of Sydenham chorea and Hashimoto thyroiditis has not been previously reported. Immunological processes are suggested to be implicated in the pathogenesis of this association; however, the exact mechanism remains unclear.