Episodes Of Hypotonia Research Articles

Altered Mental Status in a 5-year-old Girl

1. Tara M. Kopp, MD, MS* 2. Jacob M. Redel, MD†,‡ 3. Holly E. Depinet, MD, MPH§,¶ 1. *Department of Pediatrics, University of Louisville, Louisville, KY 2. †Division of Endocrinology, Children’s Mercy Hospital, Kansas City, MO 3. ‡Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 4. §Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 5. ¶Department of Pediatric, College of Medicine, University of Cincinnati, Cincinnati, OH A 5-year-old fully immunized girl with a history of tuberous sclerosis, localization-related epilepsy with remote resection of a seizure focus, developmental delay, oral aversion with gastrostomy tube dependence, and necrotizing pancreatitis presents with reported episodes of gait instability and altered mental status described as her head falling down, sudden diffuse loss of muscle tone, and unresponsiveness lasting 15 to 45 seconds. During the past few hours, the mother has noticed that the child appears wobbly. She had 1 episode of wobbliness with subsequent fall but denies any head injury, loss of consciousness, or tonic-clonic movements. On presentation to the emergency department she had 2 additional episodes of hypotonia and unresponsiveness to verbal stimuli lasting less than 1 minute. She had not recently missed any of her antiepileptic medications, which included levetiracetam, perampanel, vigabatrin, and taurine. In addition, her medications had not been changed in the past 6 months. Due to her oral aversion, her mother assures us that she would not have accidentally ingested any medications or other household substances. Initial temporal temperature is 98.2°F (36.8°C), heart rate is 124 beats/min, blood pressure is 107/77 mm Hg, respiratory rate is 24 breaths/min, and oxygen saturation is 96% on room air. Physical examination reveals a wakeful crying girl fighting medical personnel and intermittently becoming hypotonic and unresponsive to verbal commands. Mucous membranes are moist, and extremities have brisk capillary refill. Respiratory effort is normal except for episodes of periodic shallow breathing. Pupils are midline and reactive but become dilated with minimal responsiveness during the episodes of hypotonia and unresponsiveness. Upper and lower extremity hypotonia is noted (with intermittent worsening during …

Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency.

OP5 – 2696: Pyruvate dehydrogenase complex deficiency: Phenotype–genotype, phenotype–neuroimaging associations and treatment outcomes

Objectives To assess the phenotypic and genotypic spectrum of patients with pyruvate dehydrogenase complex (PDHc) deficiency, identify phenotype–genotype correlations and evaluate the effect of ketogenic diet. Methods All patients investigated at the Queen Silvia Children's Hospital and found to have genetically verified PDHc deficiency were included in this study. Results 18 patients (5 males: 13 females) were included; all but one patients were alive at a median follow-up period of 7.5 years. All patients were born at full term. Eleven patients (1 male: 10 females) presented with perinatal onset, consisting mainly of hypotonia, microcephaly and congenital lactic acidosis. These patients developed progressive microcephaly, severe mental retardation, while epilepsy was also seen in some patients. Brain neuroimaging in these patients revealed hypoplasia or complete agenesis of the corpus callosum, enlargement of the ventricles – often asymmetrical – and of the subarachnoid spaces and accompanying atrophy of the periventricular white matter. Genetic investigation showed variable genetic defects of the PDHA1 and PDHX genes. The remaining seven patients had later disease onset, at a median age of 1.5 years. The disease course in these patients pertained mainly to recurrent episodes of hypotonia, ataxia, dysarthria and hyperlactatemia, often following infections. All seven patients were found to have genetic defects in the PDHA1 gene. Brain neuroimaging showed bilateral lesions in the basal ganglia and the midbrain, while neuroimaging was normal in two patients. Thirteen patients were treated with ketogenic diet with positive effect, in the majority of treated patients, on the recurrent episodes of ataxia and dysarthria, speech development, mood and cognition. Conclusions We show that pediatric patients with PDHc deficiency express two different clinical phenotypes, each one correlated to specific neuroimaging features. The genetic background and the effect of ketogenic diet are assessed.

ATP1A3 mutations in infants: a new rapid‐onset dystonia–Parkinsonism phenotype characterized by motor delay and ataxia

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

An Infant With Ethylmalonic Encephalopathy Masquerading as a Hematologic Disorder

A 4-month-old male infant was brought to the emergency department because of striking petechial skin lesions and acrocyanosis. Routine hematology revealed leukocytosis and thrombocytosis and the infant was admitted for further investigations. Laboratory findings showed no evidence of infection, and a bone marrow aspirate demonstrated a normal number of immature cells of all lineages. Coagulation and routine biochemistry analyses were within the normal range. Three months later, the infant developed signs and symptoms of encephalopathy with episodes of hypotonia and an altered state of consciousness. A brain magnetic resonance imaging suggested the possibility of an inborn error of metabolism. The urinary organic acid and acylcarnitine profile indicated ethylmalonic encephalopathy. Mutation analysis of the ethylmalonic encephalopathy 1 (ETHE1) gene confirmed the diagnosis of ethylmalonic encephalopathy at the molecular level.