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Público·32 miembros

Autosomal Recessive Defect ((HOT))


Autosomal recessive cutis laxa is a genetically heterogeneous condition. Its molecular basis is largely unknown. Recently, a combined disorder of N- and O-linked glycosylation was described in children with congenital cutis laxa in association with severe central nervous system involvement, brain migration defects, seizures and hearing loss. We report on seven additional patients with similar clinical features in combination with congenital disorder of glycosylation type IIx. On the basis of phenotype in 10 patients, we define an autosomal recessive cutis laxa syndrome. The patients have a complex phenotype of neonatal cutis laxa, transient feeding intolerance, late closure of the fontanel, characteristic facial features including down-slanting palpebral fissures, short nose and small mouth, and developmental delay. There is a variable degree of the central nervous system involvement and variable systemic presentation. The biochemical analysis using transferrin isoelectric focusing gives false negative results in some of the youngest patients. Analysis of the apolipoprotein C-III isoelectric focusing, however, is diagnostic in all cases.




autosomal recessive defect



Autosomal recessive cutis laxa (ARCL; MIM 219200, 219100) is a genetically heterogeneous condition presenting in the newborn with loose, redundant skin folds, decreased elasticity of the skin and generalized connective tissue involvement. Abnormal elastic fiber structure and a significantly decreased amount of elastin are diagnostic findings by skin histology.1, 2 Fibulin 4 and 5 mutations have been found in some patients with ARCL.3, 4


The unique association of generalized cutis laxa, developmental and growth delay, joint and skeletal system involvement, characteristic facial features, progressive microcephaly and late closure of the fontanel has been previously described in a few children.2, 4, 5, 6 Congenital defects of glycosylation (CDG) are a group of phenotypically diverse multisystemic disorders caused by various enzyme defects of the N- (and O-linked) glycan synthesis. In some of these patients, the underlying enzyme deficiency is not yet discovered. The classification of CDG type x (MIM 212067) can be used in cases with an unknown enzyme defect in N-glycosylation.


A combined disorder of the N- and O-linked glycosylation (congenital disorder of glycosylation type IIx7) was detected in some patients with cutis laxa in combination with severe central nervous system involvement, intellectual impairment, brain migration defects, seizures and hearing loss8, 9, 10 using transferrin isoelectric focusing (TIEF) and ApoC-III isoelectric focusing (IEF) methods.11


Here we define the phenotype of the ARCL syndrome associated with a combined N- and O-linked glycan biosynthesis defect. All patients have generalized cutis laxa at birth, involving the face, trunk and extremities. Further specific findings include late closure of the fontanel, characteristic facial appearance with down-slanting palpebral fissures, short nose, small mouth and, in some of the children, joint anomalies (congenital hip dislocation, joint laxity and pes planus). These features have been described previously in the majority of patients with ARCL-II (MIM 219100). In our group, however, normal length and relative low body weight was found in most of the cases. Besides the late closure of the fontanel, no other skeletal or bone anomalies are reported by a full skeletal survey, except for decreased cranial mineralization and severe caries in two females. None of the patients developed occipital horns, a characteristic feature in the X-linked form of syndromic cutis laxa (MIM 304150).


The phenotypic variability regarding growth and development could be the consequence of consanguinity; however, it still highlights the usefulness of glycosylation studies in the diagnosis of ARCL-II. It remains open for further investigations whether ARCL-II is heterogeneous and may occur both with and without glycosylation abnormalities. In our patient group demonstrating a distinct clinical and biochemical phenotype, however, we were able to detect the same underlying genetic defect.


All of the children described in our report have a combined disorder of glycosylation with a characteristic TIEF pattern (CDG type II) and an abnormal isofocusing profile for core 1 mucin type O-glycan in blood, demonstrated by the abnormal results of the ApoC-III IEF. The pattern is different from the severe hypoglycosylation observed in COG gene defects,21, 22 but there is an obvious increased level of the ApoC-III1 fraction and decreased levels of ApoC-III2.


Here we define an ARCL syndrome with a combined congenital defect of N- and O-linked glycosylation. We suggest evaluating the protein glycosylation status in all children with congenital wrinkled skin or cutis laxa, especially with characteristic facial features, late closure of the fontanel, variable central nervous system involvement and developmental delay.


Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation. The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (


Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or fatigability in adulthood [1]. There is a considerably broad phenotypic range associated with this condition, ranging from early infantile decompensation to adults who are asymptomatic, therefore, establishing the diagnosis early is essential to guide management. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (


CDSP is an autosomal recessive condition; therefore, we would expect the disorder to occur with equal frequency in males and females. However, apparent sex ratio may be skewed because more adult women may be diagnosed secondary to their infants being diagnosed with CDSP and more adult women than men may actually experience symptoms related to CDSP, particularly during pregnancy which can exacerbate symptoms.


Carnitine (3-hydroxy-4-trimethylaminobuyric acid) is mostly derived from dietary intake, but can also be synthesized from lysine and methionine in the liver and kidney. Carnitine is required for the transfer of long-chain fatty acids from the cytoplasm into the mitochondria for beta oxidation [5]. During periods of fasting, fatty acids are the predominant source of energy production. Thus, if carnitine is deficient, this will result in defective fatty acid oxidation. When fat cannot be utilized glucose is consumed without regeneration via gluconeogenesis resulting in hypoglycemia. In addition, fat released from adipose tissue accumulate in the liver, skeletal muscle, and heart resulting in hepatic steatosis and myopathy [2].


CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic cation transporter type 2 (OCTN2), which is part of a larger family of OCTNs that play a significant role in transporting organic cation compounds across cell membranes. OCTN2 transfers carnitine across the cell membrane in a sodium-dependent manner. When OCTN2 is not working properly, this can result in improper transfer of carnitine across the cell membrane resulting in a) urinary carnitine wasting leading to low plasma carnitine levels, and b) decreased intracellular carnitine accumulation.


CDSP should be differentiated from secondary causes of carnitine deficiency. Several groups of inherited metabolic disorders can cause carnitine deficiency, including, organic acidemias and fatty acid oxidation defects such as very long chain acyl-CoA dehydrogenase (VLCAD), medium-chain acyl-CoA dehydrogense (MCAD), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), and carnitine palmitoyltransferase II (CPT II) deficiencies. CDSP can be differentiated from other fatty acid oxidation defects by demonstration of very low free carnitine levels in plasma (C0) with normal acylcarnitine profile (the concentration of different length acylcarnitine species).


There are reports of individuals with the confirmed diagnosis of CDSP being asymptomatic. The limited literature regarding asymptomatic adults with CDSP and potential health risks make it unclear if treatment in this population is indicated or warranted. However, based on experience with other fatty acid oxidation defects such as medium-chain acyl CoA dehydrogenase (MCAD) deficiency, where individuals can be asymptomatic throughout their life until they have an acute episode during times of stress or illness, and then die suddenly, it has been suggested that carnitine supplementation in asymptomatic individuals with CDSP should be initiated [1]. Diet provides approximately 75% of daily carnitine requirement. This may play a role in modulating the variability and severity of features in individuals with CDSP, especially in those who remain asymptomatic throughout their lifetime.


A number sign (#) is used with this entry because autosomal recessive thrombophilia due to protein S deficiency (THPH6) is caused by homozygous or compound heterozygous mutation in the gene encoding protein S (PROS1; 176880) on chromosome 3q11.


Autosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), whereas others have recurrent thromboses later in childhood (Comp et al., 1984). 041b061a72


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