Lead Encephalopathy with Distinctive Brain Magnetic Resonance Imaging Findings.

Lead poisoning is a multisystem disorder, more commonly affecting children. Occupational exposure, traditional medicines, and contaminated alcohol have been associated with lead encephalopathy in adults. Herein, we report a patient of lead toxicity presenting to the emergency services as acute encephalopathy with symptomatic hyponatremia and chronic recurrent abdominal colic and vomiting. This 50-year-old battery mechanic had multisystem involvement with anemia, basophilic stippling, lead line on the gums, and chronic hypertension. The blood lead level was more than 65 mcg/dL. Computed tomography of the brain showed intracranial calcifications and the MRI brain showed bilateral symmetric involvement of the thalamus, basal ganglia, brainstem, and external capsule. His sensorium improved rapidly after the correction of hyponatremia, however, apathy and psychomotor slowing persisted. This case highlights the importance of recognizing clinical markers and characteristic imaging findings, which can provide clues to an early diagnosis of this otherwise rare clinical condition, and prompt chelation therapy and avoid further lead exposure.

A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients.

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing-based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

Nemaline Rod/Cap Myopathy Due to Novel Homozygous MYPN Mutations: The First Report from South Asia and Comprehensive Literature Review.

BACKGROUND AND PURPOSE: Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. METHODS: A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on a 1.5-T device in patient 1. RESULTS: Two unrelated adults born to consanguineous parents, a 28-year-old male and a 23-year-old female, were diagnosed with pathogenic variants in MYPN that cause cap myopathy. Both patients presented with early-onset, insidiously progressive, and minimally disabling proximodistal weakness with mild ptosis, facial weakness, and bulbar symptoms. Patient 1 had a prominent foot drop from the onset. Both patients were followed up at age 30 years, at which point serum creatine kinase concentrations were minimally elevated. There were no cardiac symptoms; electrocardiograms and two-dimensional echocardiograms were normal in both patients. Muscle MRI revealed preferential involvement of the glutei, posterior thigh muscles, and anterior leg muscles. Whole-exome sequencing revealed significant homozygous splice-site variants in both of the probands, affecting intron 10 of MYPN: c.1973+1G>C (patient 1) and c.1974-2A>C (patient 2). CONCLUSIONS: This study elaborates on two patients with homozygous MYPN pathogenic variants, presenting as slowly progressive congenital myopathy. These patients are only the tenth and eleventh cases reported in the English literature, and the first from South Asia. The clinical phenotype reiterates the mild form of nemaline rod/cap myopathy. A comprehensive literature review is presented.

Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

Altered REM sleep architecture in patients with Myotonic dystrophy type 1: is related to sleep apnea?

OBJECTIVE: To determine the sleep architecture and sleep respiratory abnormalities and to correlate with sleep symptoms in patients with Myotonic dystrophy type 1 (DM1). METHODS: We recruited a cohort of genetically confirmed patients with DM1, who attended the Neuromuscular clinic between July 2016 and December 2019. Clinical, sleep and whole night polysomnography data were collected. The analysis of sleep architecture, sleep respiratory parameters and comparison with healthy controls (HC) was performed in our sleep laboratory. RESULTS: A total of 59 patients with DM1 underwent sleep evaluation. Hypersomnolence in 42 (77.8%), ESS>10 in 23 (39%), and PSQI>5 in 18 (30.5%) were found in patients with DM1. Thirty-one (68.89%) patients with DM1 and 22 (95.65%) HC had more than 4-h of total sleep time (TST). More than 4 h of TST was taken to compare respiratory and sleep architecture parameters. Patients with DM1 had reduced sleep efficiency, reduced N2 sleep, and increase in N1 sleep, wake index, stage shift index, nocturnal sleep-onset REM periods compared to HC. AHI>15 was found in 16 (51.61%) DM1 and in 3 HC (13.64%). AHI had positive correlation with BMI, but not with age, ESS or disease progression (MIRS). All DM1 with AHI>15; 8(80%) and 1(33.33%) in AHI5to15, and AHI<5 groups, respectively had hypersomnolence. CONCLUSION: In this first study on Indian cohort, daytime hypersomnolence, poor nocturnal sleep quality, sleep architecture irregularities are identified to be common in patients with DM1. These abnormalities may be explained by sleep-related breathing disorders that are highly prevalent in these patients.

Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies.

BACKGROUND AND PURPOSE: Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. METHODS: We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. RESULTS: We found that patients presented with variable disease severity at different ages of onset (8-25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5-associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot-Marie-Tooth disease. CONCLUSIONS: PLEKHG5-associated neuropathies should be considered as an important differential in non-5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5-associated diseases.

Social Cognition Deficits Are Pervasive across Both Classical and Overlap Frontotemporal Dementia Syndromes.

OBJECTIVES: Frontotemporal dementia (FTD) syndromes are a complex group of disorders characterised by profound changes in behaviour and cognition. Many of the observed behavioural abnormalities are now recognised to be due to impaired social cognition. While deficits in emotion recognition and empathy are well-recognised in behavioural-variant (Bv)FTD, limited information exists about the nature of social cognitive impairment in the language variant primary progressive aphasia (PPA) that includes progressive non-fluent aphasia (PNFA) and semantic dementia (SD), and in the motor variants FTD amyotrophic lateral sclerosis (FTD-ALS) and FTD progressive supranuclear palsy (FTD-PSP). This prospective study sought to explore the nature and profile of social cognition deficits across the spectrum of FTD. METHODS: Sixty patients on the FTD spectrum, i.e., classical (16 with BvFTD and 20 with PPA) and overlap FTD syndromes (13 with FTD-ALS and 11 with FTD-PSP) were evaluated by means of the social cognition tasks, the Interpersonal Reactivity Index (IRI) for empathy, and pictures of facial affect (POFA) for emotion recognition. General cognition and behaviour were also assessed. RESULTS: A significant impairment in emotion recognition and empathy was detected in both the classical and overlap FTD syndromes. The recognition of positive emotions was relatively preserved compared to that of negative emotions. Among the FTD subtypes, maximal impairment of empathy was demonstrated in FTD-PSP. CONCLUSION: Social cognition impairment is pervasive across the spectrum of FTD disorders, and tests of emotion recognition and empathy are clinically useful to identify the nature of behavioural problems in both classical and overlap FTD. Our findings also have implications for understanding the neural basis of social cognition in FTD.