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)

Toriello-Carey is a rare multiple malformation/mental retardation syndrome characterized by dysmorphic features, including telecanthus/hypertelorism, short palpebral fissures, a small nose with anteverted nares, malformed ears, and a Pierre Robin sequence. Affected patients also show several other important signs of midline field disruption: agenesis of the corpus callosum, laryngeal anomalies, and congenital heart defects. Hypotonia and developmental delay are present in most reported cases. Autosomal recessive inheritance was proposed, but an X-linked or sex-influenced gene disorder was also suspected. We report on two siblings, a brother and sister, supporting further an autosomal recessive type of inheritance. Both patients had severe clinical presentation with death in early infancy. Besides clinical findings typical for this condition, they showed additional traits, expanding further the phenotypic spectrum. A specific malformation pattern observed in the patients presented and, in the previously reported cases, suggests an early midline developmental field disruption, presumably caused by a developmental regulatory gene mutation.
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PMID:Further delineation of the Toriello-Carey syndrome: a report of two siblings. 1249 42

X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.
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PMID:Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP. 1536 6

We describe two brothers born to consanguineous parents, who presented with hypotonia and hypoglycaemia in the neonatal period and later developed obesity and developmental delay. They had brachydactyly and similar facial features including a prominent forehead, low nasal bridge, midface hypoplasia, full lips, a small mouth, and small, low set ears with overfolded helices. Their sister had mild learning disabilities. No additional anomalies were found, and metabolic investigations including peroxisomal functions gave normal results. We suggest the patients have a hitherto unreported condition, with an autosomal or X-linked mode of inheritance.
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PMID:Midface hypoplasia, obesity, developmental delay and neonatal hypotonia in two brothers. 1251 59

X-linked myotubular myopathy is characterised by neonatal hypotonia, muscle weakness and respiratory distress in affected males, leading often to early death, although prolonged survival is observed in milder forms, or as a result of prolongation of ventilation support. It is caused by mutations in the MTM1 gene, which encodes a phosphatase called myotubularin, which has been highly conserved during evolution, down to yeasts ( S. cerevisiae and S. pombe). To date, 251 mutations have been identified in unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene. We have found additional mutations in 77 patients, including 35 novel ones. We identified a missense mutation N180K in a 67-year-old grandfather (the oldest known patient with an MTM1 mutation), previously suspected to have autosomal centronuclear myopathy, and in his two grandsons also mildly affected. Mild and moderate phenotypes associated with novel missense mutations and with a translation initiation defect mutation are discussed, as well as severe phenotypes associated with particular novel mutations. With the present report, 192 different mutations in the MTM1 gene have been described in 328 families. The spectrum of mutations is now enlarged from the very severe classic neonatal phenotype to very mild phenotype allowing survival to the age of 67 years.
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PMID:Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. 1252 54

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.
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PMID:Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 1261 69

We report the cases of two male preterm newborns with X-linked centronuclear myopathy (CNM). This is the most severe type of CNM. Each of them presented with generalized hypotonia, weakness, difficulty in swallowing, and respiratory distress at birth. Physical examination of both newborns revealed long thin face, high-arched palate, mild bilateral ptosis, frog-leg posture, and absence of deep tendon reflex. Diagnosis of the disease was made according to fetal history, family history, muscle histopathology, electron microscopy, and genetic analysis. Subdural hemorrhage of brain and subcapsular hematoma of the liver were found at autopsy of Case 1. The results of molecular analysis of Case 2 and his family favored the diagnosis of X-linked CNM. Molecular studies can be easily performed with only minute amount of DNA of patients, and may help the clinician to predict which patients may be at the risk for medical complications.
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PMID:X-linked centronuclear myopathy. 1287 27

Polyamines (putrescine, spermidine, spermine) are ubiquitous, simple molecules that interact with a variety of other molecules in the cell, including nucleic acids, phospholipids and proteins. Various studies indicate that polyamines are essential for normal cell growth and differentiation. Furthermore, these molecules, especially spermine, have been shown to modulate ion channel activities of certain cells. Nonetheless, little is known about the specific cellular functions of these compounds, and extensive laboratory investigations have failed to identify a heritable condition in humans in which polyamine synthesis is perturbed. We report the first polyamine deficiency syndrome caused by a defect in spermine synthase (SMS). The defect results from a splice mutation, and is associated with the Snyder-Robinson syndrome (SRS, OMIM_309583), an X-linked mental retardation disorder. The affected males have mild-to-moderate mental retardation (MR), hypotonia, cerebellar circuitry dysfunction, facial asymmetry, thin habitus, osteoporosis, kyphoscoliosis, decreased activity of SMS, correspondingly low levels of intracellular spermine in lymphocytes and fibroblasts, and elevated spermidine/spermine ratios. The clinical features observed in SRS are consistent with cerebellar dysfunction and a defective functioning of red nucleus neurons, which, at least in rats, contain high levels of spermine. Additionally, the presence of MR reflects a role for spermine in cognitive function, possibly by spermine's ability to function as an 'intrinsic gateway' molecule for inward rectifier K(+) channels.
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PMID:X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. 1450 4

MTM1, MTMR2, and SBF2 belong to a family of proteins called the myotubularins. X-linked myotubular myopathy, a severe congenital disorder characterized by hypotonia and generalized muscle weakness in newborn males, is caused by mutations in MTM1 (Laporte et al., 1996). Charcot-Marie-Tooth types 4B1 and 4B2 are severe demyelinating neuropathies caused by mutations in MTMR2 (Bolino et al., 2000) and SBF2/MTMR13 (Senderek et al., 2003), respectively. Although several myotubularins are known to regulate phosphoinositide-phosphate levels in cells, little is known about the actual cellular process that is defective in patients with these diseases. Mutations in worm MTM-6 and MTM-9, myotubularins belonging to two subgroups, disorganize phosphoinositide 3-phosphate localization and block endocytosis in the coelomocytes of Caenorhabditis elegans. We demonstrate that MTM-6 and MTM-9 function as part of a complex to regulate an endocytic pathway that involves the Arf6 GTPase, and we define protein domains required for MTM-6 activity.
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PMID:Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans. 1456 69

Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2 are two sides of the same coin. Both arise from mutations in the gene encoding myelin proteolipid protein. The disease spectrum for Pelizaeus-Merzbacher disease and spastic paraplegia type 2 is extraordinarily broad, ranging from a spastic gait in the pure form of spastic paraplegia type 2 to a severely disabling form of Pelizaeus-Merzbacher disease featuring hypotonia, respiratory distress, stridor, nystagmus, and profound myelin loss. The diverse disease spectrum is mirrored by the underlying pathogenesis, in which a blockade at any stage of myelin proteolipid protein synthesis and assembly into myelin spawns a unique phenotype. The continuing definition of pathogenetic mechanisms operative in Pelizaeus-Merzbacher disease and spastic paraplegia type 2, together with advances in neural cell transplant therapy, augurs well for future treatment of the severe forms of Pelizaeus-Merzbacher disease.
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PMID:Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. 1457 40

Oligophrenin-1 (OPHN-1) gene disruption is known as responsible for so called "non-specific" X-linked mental retardation (MR) Billuart et al. [1998: Nature 392:923-926]. In order to search for a possible specific clinical and radiological profile for mutation in the OPHN-1 gene, clinical and 3D brain MRI studies were performed in the two families with a known mutation in OPHN-1 reported so far: a 19-year-old female with an X;12 balanced translocation encompassing OPHN-1, and four affected males of family MRX60 sharing a frameshift mutation in OPHN-1. Clinical data shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early onset complex partial seizures, and moderate to severe MR. Brain MRIs performed in three individuals exhibited a specific vermian dysgenesis including an incomplete sulcation of anterior and posterior vermis with the most prominent defect in lobules VI and VII. In addition, a non-specific cerebral cortico-subcortical atrophy was also observed. These clinical and radiological features suggest a distinct clinico-radiological syndrome. These preliminary data need to be confirmed in other families and will be helpful for further targeted mutation screening of the OPHN-1 gene in male patients with similar clinico-radiological features. In addition, OPHN-1 inactivation should be considered as a relevant model of developmental vermis disorganization, leading to a better understanding of the possible role of the cerebellum in MR.
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PMID:Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene. 1473 83


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