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3 results on '"Keith Hyland"'

1. Intermittent neurologic decompensation: An underrecognized presentation of tyrosine hydroxylase deficiency

Author

Marjolaine Champagne, Gabriella A. Horvath, Sébastien Perreault, Julie Gauthier, Keith Hyland, Jean‐François Soucy, and Grant A. Mitchell

Subjects
neurological decompensation, TH, tyrosine hydroxylase deficiency, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470
Abstract

Abstract Tyrosine hydroxylase deficiency (THD) is a treatable inborn error of dopamine biosynthesis caused by mutations in TH. Two presentations are described. Type A, milder, presents after 12 months of age with progressive hypokinesis and rigidity. Type B presents before 12 months as a progressive complex encephalopathy. We report a girl with mild THD who had recurrent episodes of neurological decompensations. Before the first episode, she had normal development except for mild head tremor. Episodes occurred at 12, 19, and 25 months of age. After viral infections or vaccination, she developed lethargy, worsened tremor, language, and motor regression including severe axial hypotonia, recuperating over several weeks of intensive rehabilitation but with residual tremor and mild lower limb spasticity. Basal ganglia imaging was normal. Exome sequencing revealed two missense variants of uncertain significance in TH: c.1147G>T and c.1084G>A. Both have low gnomAD allele frequencies and in silico, are predicted to be deleterious. Cerebrospinal fluid analysis showed low homovanillic acid (HVA, 160 nmol/L, reference 233–938) and low HVA/5‐hydroxyindolacetic acid molar ratio (1.07, reference .5–3.5). She responded rapidly to L‐Dopa/carbidopa without further episodes. Literature review revealed four other THD patients who had a total of seven episodes of marked hypotonia and motor regression following infections, occurring between ages 12 months and 6 years. All improved with L‐Dopa/carbidopa treatment. Intermittent THD is treatable, important for genetic counseling, and should be considered after even a single episode of marked hypotonia with recuperation over weeks, especially in patients with preexisting tremor, dystonia, or rigidity.

Published
2022
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2. Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy

Author

Elsa Rossignol, Paola Diadori, Anne-Marie Laberge, Stephane Camuzeaux, Grant A. Mitchell, Peter E. Clayton, Alina Levtova, Pierre Allard, Keith Hyland, Catherine Brunel-Guitton, and Philippa B. Mills

Subjects
medicine.medical_specialty, Pathology, business.industry, Homovanillic acid, PNPO, Neonatal onset, Status epilepticus, medicine.disease, Pyridoxine, Article, chemistry.chemical_compound, Endocrinology, Cerebrospinal fluid, chemistry, Inborn error of metabolism, Internal medicine, medicine, medicine.symptom, business, Pyridoxal, medicine.drug
Abstract

Deficiency of pyridox(am)ine 5′-phosphate oxidase (PNPO, OMIM 610090) is a treatable autosomal recessive inborn error of metabolism. Neonatal epileptic encephalopathy and a low cerebrospinal fluid (CSF) pyridoxal 5′-phosphate level are the reported hallmarks of PNPO deficiency, but its clinical and biochemical spectra are not fully known. Case presentation: A girl born at 33 3/7 weeks of gestation developed seizures in the first hours of life. Her seizures initially responded to GABAergic agonists, but she subsequently developed a severe epileptic encephalopathy. Brain MRI and infectious and metabolic evaluations at birth, including urinary alpha-aminoadipic semialdehyde (AASA), were normal. Lumbar puncture at age 3 months showed: pyridoxal 5′-phosphate, 52 nmol/L (normal, 23–64); homovanillic acid, 392 nmol/L (normal, 450–1,132); 5-hydroxyindoleacetic acid, 341 nmol/L (normal, 179–711); and 3-ortho-methyldopa, 30 nmol/L (normal, below 300). The patient was not being treated with pyridoxine nor with pyridoxal 5′-phosphate at the time of the lumbar puncture. She died at age 14 months. A sequencing panel targeting 53 epilepsy-related genes revealed a homozygous missense mutation in PNPO (c.674G>A, p.R225H). Homozygosity was confirmed by parental testing. Expression studies of mutant p.R225H PNPO revealed greatly reduced activity. In conclusion, a normal CSF level of pyridoxal 5′-phosphate does not rule out PNPO deficiency.

Published
2014

3. Levodopa response reveals sepiapterin reductase deficiency in a female heterozygote with adrenoleukodystrophy

Author

Florian Eichler, Joe Chiles, Steven J. Steinberg, Ronald L. Thibert, and Keith Hyland

Subjects
Genetics, medicine.medical_specialty, Mutation, Levodopa, business.industry, Very long chain fatty acid, Heterozygote advantage, medicine.disease_cause, medicine.disease, Hypotonia, Article, chemistry.chemical_compound, Endocrinology, Sepiapterin reductase deficiency, chemistry, Internal medicine, medicine, Adrenoleukodystrophy, medicine.symptom, Sepiapterin reductase, business, medicine.drug
Abstract

We report a 4-year-old girl heterozygous for X-linked adrenoleukodystrophy (ALD) who displayed dopa-responsive motor symptoms and was subsequently diagnosed with sepiapterin reductase deficiency (SPR; OMIM 182125). Her father and paternal uncle had known ALD, and she was found to have elevated plasma very long chain fatty acids and a mutation in the ABCD1 gene. She had language delay, severe hypotonia and abnormal eye movements and responded dramatically to a trial of levodopa (4 mg/kg per day). Two mutations within the gene for sepiapterin reductase were found and cultured skin fibroblasts demonstrated near zero activity of the enzyme. This case illustrates the importance of treatment trials that may give rise to biochemical clues to the underlying diagnosis, and the need to continue to search for diagnoses despite a misleading family history.

Published
2011

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