Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two siblings, a 27-year-old man and his 24-year-old sister were diagnosed with classic transferase deficiency galactosemia at birth and were treated with strict lactose restriction. Despite well-documented dietary management, both siblings are mentally retarded and manifest a progressive neurologic condition characterized by hypotonia, hyperreflexia, dysarthria, ataxia, and a postural and kinetic tremor. Magnetic resonance imaging revealed moderate cortical atrophy, a complete lack of normal myelination, and multifocal areas of increased signal in the periventricular white matter on T2-weighting. These patients suggest that even with early diagnosis and treatment, individuals with galactosemia may have significant neurologic morbidity with abnormalities of white matter development. This finding raises the possibility of biochemical heterogeneity within the classic transferase deficiency group, as well as the possibility of a lack of available galactose metabolites necessary for glycolipid synthesis causing a disruption of normal myelin development.
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PMID:Neurologic complications in galactosemia. 162 20

We report on five girls (including monozygotic twins) with a newly recognized disease comprising severe neurologic disturbances, variable hepatomegaly, abnormal subcutaneous fat distribution and skeletal anomalies. The neurologic picture was characterized by moderate to severe psychomotor retardation, alternating internal strabismus , hypotonia, hyporeflexia and ataxia. Biochemical investigations showed a number of abnormalities such as tubular proteinuria, slightly increased serum transaminases, hypoalbuminemia, hypo-beta-lipoproteinemia and decreased serum thyroxine-binding globulin. Moreover there was retinitis pigmentosa, cerebellar hypotrophy and electrophysiologic evidence for a peripheral neuropathy. However, histologic examination of a nerve biopsy in one of the patients failed to show myelin abnormalities. On the other hand, abnormal lamellar inclusions were found in the lysosomes of some Schwann cells and of liver tissue as well. Additional investigations in four patients revealed a deficiency of sialic acid, galactose and N-acetylglucosamine of plasma glycoproteins. Enzymatic analysis of serum suggested a deficiency of an N-acetyl-glucosaminyltransferase. Remarkably, the (healthy) fathers but not the mothers presented the same carbohydrate deficiencies of plasma glycoproteins albeit to a much lesser degree. The mode of hereditary transmission of this disease remains unclear; the possibility of X-linked inheritance is under investigation.
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PMID:[A not-previously described hereditary neurological disease with a deficiency of sialic acid, galactose and N-acetylglucosamine of plasma glycoproteins]. 260 46

Forty patients with the Prader-Willi syndrome have been examined. The typical features begin in gestational life with poor fetal vigor and difficulties with birth and post-partum feeding. The classical features of hypotonia, small hands and feet, cryptorchidism can be identified at this time. The delayed milestones, mental retardation and obesity become more prominent later. The average height of the patients in this series who were admitted to the Clinical Study Center was 149 cm and their weight was 114 kg. The weight and height curves show that Prader-Willi individuals are consistently shorter and heavier than normal children. Tests of endocrine function showed normal glucose tolerance. Insulin secretion was increased in relation to obesity. The rise in growth hormone (hGH) after injecting insulin to induce hypoglycemia and after the infusion of arginine was comparable to other obese individuals but was low in comparison to normal weight subjects. There was no rise in growth hormone with L-dopa administration, but there was a rise in hGH with the administration of 2-deoxy-D-glucose. The hypoglycemia produced by insulin was greater in the Prader-Willi patient than in obese controls. The rise in TRH (thyrotropin-releasing hormone) following the injection of TSH (thyrotropin stimulating hormone) was greater in the Prader-Willi patients than in the obese controls. Hypogonadism was routine in this series, and the response to LRH (luteinizing releasing hormone) was absent in all tested subjects. Treatment with clomiphene for 30 to 90 days significantly increased the response to LRH in three adult individuals who had not been treated with gonadal steroids previously and who were hypogonadal. Rectal temperature declined in three of the five Prader-Willi patients during exposure to an ambient temperature of 4 degrees C, but none of the three obese controls showed a decline. Food intake averaged 5167 kcal/d when six patients were given trays containing more food than they could eat. Food intake was not reduced when tryptophan was added to the diet. Salivary secretion was reduced in the Prader-Willi patients. A number of pulmonary function tests were significantly reduced in the study patients compared to obese or normal weight controls. The anatomic findings in four autopsied patients with the Prader-Willi syndrome showed no significant differences from those of obese subjects without this syndrome. The chromosomal pattern showed a deletion or translocation at chromosome 15 in 3 of 12 patients in whom this test was performed. These findings in 40 patients with the Prader-Willi syndrome have been compared with the information contained in 159 reports published in the medical literature.
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PMID:The Prader-Willi syndrome: a study of 40 patients and a review of the literature. 633 43

We report on a 13-year-old girl with late infantile neuronal ceroid lipofuscinosis (NCL) in whom PET scanning with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]/FDG) was performed. Early psychomotor development was normal. At the age of 2 years, neurological signs such as hypotonia and incoordination appeared, followed by visual failure and ataxia. At the age of 4, funduscopic examination showed macular degeneration and papillary atrophy. At the age of 9, myoclonic jerks were observed; subsequently, generalized seizures together with failing vision, mental deterioration, and visual and auditory hallucinations appeared. Brain MRI showed severe cortical and subcortical atrophy. A skin biopsy detected the presence of 'finger-print' inclusions in the cytoplasm of smooth muscle fibers. Late infantile NCL (Jansky-Bielschowsky disease) was diagnosed. FDG/PET revealed a severe reduction of metabolism in all the cortical and subcortical structures. A regional analysis of the distribution of the tracer revealed marked bilateral hypometabolism, particularly in calcarine, lateral, occipital, and temporal cortices and in the thalamus.
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PMID:Positron emission tomography in neuronal ceroid lipofuscinosis (Jansky-Bielschowsky disease): a case report. 757 68

An 8-year-old boy with galactose-1-phosphate uridyl transferase (GALT) deficiency presented with hypotonia, muscle hypotrophy, hepatomegaly, bilateral cataract and mild mental retardation. Two brothers showed a GALT activity consistent with a homozygotic condition and both parents were found to be heterozygotes for this defect. Histological and ultrastructural examination of muscle biopsy specimens showed several necrotic fibres. GALT activity was undetectable in skeletal muscle and muscle tissue cultures; myotubes converted galactose to CO2 at a lower rate than controls. Galactose-1-phosphate was increased in the patient's red cells and muscle tissue. GALT deficiency, not previously described in muscle, may be of pathogenic relevance in determining the myopathic features present in GALT deficiency syndrome.
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PMID:Clinical and biochemical evidence of skeletal muscle involvement in galactose-1-phosphate uridyl transferase deficiency. 832 30

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken syndrome) is the prototype of a class of genetic multisystem disorders characterized by defective glycosylation of glycoconjugates. It is mostly a severe disorder which presents neonatally. There is a severe encephalopathy with axial hypotonia, abnormal eye movements and pronounced psychomotor retardation, as well as a peripheral neuropathy, cerebellar hypoplasia and retinitis pigmentosa. The patients show a peculiar distribution of subcutaneous fat, nipple retraction and hypogonadism. There is a 20% lethality in the first years of life due to severe infections, liver insufficiency or cardiomyopathy. CDG1 shows an autosomal recessive mode of inheritance and has been mapped to chromosome 16p. Most patients show a deficiency of phosphomannomutase (PMM)8, an enzyme necessary for the synthesis of GDP-mannose. We have cloned the PMM1 gene, which is on chromosome 22q13 (ref.9). We now report the identification of a second human PMM gene, PMM2, which is located on 16p13 and which encodes a protein with 66% identity to PMM1. We found eleven different missense mutations in PMM2 in 16 CDG1 patients from different geographical origins and with a documented phosphomannomutase deficiency. Our results give conclusive support to the biochemical finding that the phosphomannomutase deficiency is the basis for CDG1.
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PMID:Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). 914 Apr 1

Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly delineated group of inherited multisystemic disorders associated with abnormal glycosylation of a number of serum glycoproteins. Several types have been described on the basis of clinical presentation and biochemical changes of the glycosylation of serum transferrin and attributed to different enzymatic defects; their clinical presentations are fully different and a clinical heterogeneity is observed within a same type of CDGS. Patients with CDGS type la usually present with neurologic (hypotonia, strabismus and cerebellar hypoplasia) and cutaneous (inverted nipples, abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, hepatic, cardiac, renal). However, neurologic and cutaneous symptoms may be absent, so that CDGS must be looked for in case of unexplained organ failure such as isolated liver insufficiency, cardiomyopathy, pericarditis, tubulopathy, nephrotic syndrome, vascular accident or retinitis pigmentosa. Patients with CDGS type Ib present with liver disease, enteropathy and hypoglycemia without neurologic involvement. These patients are successfully treated with oral mannose administration emphasizing the importance of making the diagnosis. Patients with CDGS type Ic present with mild psychomotor retardation and seizures. Patients with CDGS type II have psychomotor retardation association with severe gastrointestinal disorder, dysmorphic features and abnormal electroretinogram. Other types (III, IV) are less clearly defined and the clinical presentation includes convulsive encephalopathy. Biological abnormalities such as mild hepatic cytolysis, hematologic and hormonal abnormalities are consistently observed in CDGS type I, as well as renal hyperechogeneity, leading one to look for this syndrome when they are associated. Until now, only four enzymatic deficiencies have been identified (types Ia, Ib, Ic, II).
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PMID:[Carbohydrate-deficient blood glycoprotein syndrome]. 1070 Oct 64

The Ehlers-Danlos syndromes are a heterogeneous group of inherited connective tissue disorders that are characterized by joint hypermobility and skin fragility and hyperextensibility. Patients with the autosomal recessive type VI variant of the Ehlers-Danlos syndromes (EDS VI), also classified as the kyphoscoliotic type, are clinically characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. Biochemically, this has been attributed to a deficiency of lysyl hydroxylase (LH), an important posttranslational modifying enzyme in collagen biosynthesis. This enzyme hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines which have two important functions. The residues serve as attachment sites for galactose and glucosylgalactose and they also act as precursors of the crosslinking process that gives collagen its tensile strength. At least 20 different mutations have been identified in the LH1 gene (the originally described form) that contribute to LH deficiency and the clinical characteristics of EDS VI. Two of these mutations, a large duplication of exons 10-16, arising from a homologous recombination of intronic Alu sequences, and a nonsense mutation, Y511X, in exon 14 of the LH1 gene, have been identified in five or more unrelated patients. Both mutations appear to have originated from a single ancestral gene. Alternative processing pathways involving alternate splicing and mRNA degradation, which reduce the effect of the mutant allele and restore partial activity of the enzyme, have been identified. A second class of EDS VI has been proposed in which patients have the clinical phenotype of EDS VI but their levels of LH activity are normal. The biochemical basis for this form of EDS VI is currently unknown.
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PMID:Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. 1100 13

Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <--> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly. The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations. The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians.
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PMID:Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. 1135 Jan 85

Defects in the assembly of dolichol-linked oligosaccharide or its transfer to proteins result in severe, multi-system human diseases called Type I congenital disorders of glycosylation. We have identified a novel CDG type, CDG-Ij, resulting from deficiency in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1. The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia. Metabolic labeling of cultured dermal fibroblasts from the patient with [2-(3)H]-mannose revealed lowered incorporation of radiolabel into full-length dolichol-linked oligosaccharides and glycoproteins. In vitro enzymatic analysis of microsomal fractions from the cultured cells indicated that oligosaccharyltransferase activity is normal, but the GPT activity is reduced to approximately 10% of normal levels while parents have heterozygous levels. The patient's paternal DPAGT1 allele contains a point mutation (660A>G) that replaces a highly conserved tyrosine with a cysteine (Y170C). The paternal allele cDNA produces a full-length protein with almost no activity when over-expressed in CHO cells. The maternal allele makes only about 12% normal mature mRNA, while the remainder shows a complex exon skipping pattern that shifts the reading frame encoding a truncated non-functional GPT protein. Thus, we conclude that the DPAGT1 gene defects are responsible for the CDG symptoms in this patient. Hum Mutat 22:144-150, 2003.
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PMID:Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. 1287 55


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