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PubMed1977

[Comparative analysis of the clinico-constitutional and premorbid features of epilepsy in inbred and outbred families].

By means of clinico-catamnestical and anthropological methods the author examined 162 epileptic patients in the initial period (up to 5 years) and 473--in the florid period of the disease (5--24 years). The author demonstrates distinct clinical (the traits of the onset, development of the process, personality changes, invalidization), morphological (dysgenesia) and premorbid characterological and intellectual traits in patients of consanguineous and nonconsanguineous families. The results demonstrate a correlation between the fenotypical traits of epilepsy and the constitutional morphological and premorbid features. The achieved data point to the necessity of a differentiated approach to therapeutical measures and sociolabour rehabilitation in patients of consanguineous and nonconsanguineous families.

Adolescent↗
PubMed1996

[Adhalin gene mutations in malignant limb-girdle muscular dystrophy and clinical features in adhalin-deficient muscular dystrophy].

We have reported adhalin gene mutations in 4 patients from 3 families with malignant limb-girdle muscular dystrophy (MLGMD), and summarized the clinical features in adhalin-deficient muscular dystrophy (ADMD) reported as severe childhood autosomal recessive muscular dystrophy (SCARMD) in the English literatures. Adhalin cDNA amplified from RNA by reverse transcription polymerase chain reaction (RT-PCR) was sequenced in 3 patients from 2 consanguinous families (Wa. and Ta.) with MLGMD who showed immunohistochemically a complete deficiency of adhalin in the skeletal muscle, and adhalin genomic DNA amplified by PCR was sequenced in 1 patient from a non-consanguinous family (Ma.). In one patient from family Wa., a cytosine to thymine substitution at nt. 229 was identified in the adhalin gene, resulting in the replacement of Arg by Cys at codon 77. In two patients from family Ta., an adenine to guanine substitution at nt. 410 and an insertion of 15 bases between nt. 408 and 409 were identified, resulting in Glu to Gly replacement at codon 137 and insertion of a peptide with 5 amino acids. In one patient from family Ma., a deletion of adenine at nt. 404 or nt. 405 and a thymidine to cytosine substitution at nt. 470 were identified. These amino acid replacements are expected to change the secondary and tertiary structure, which may affect the interaction of adhalin with other dystrophin-associated glycoproteins and basal lamina, and may subsequently cause the degeneration of muscle fibers. Sixty-six cases from 49 families with ADMD have been reported in the literature. Compared with patients with Duchenne muscular dystrophy (DMD), patients with ADMD were older in age at the time of onset or loss of ambulation. Mental retardation and cardiac dysfunction were rarely observed in ADMD patients. On muscle histology, the number of necrotic fibers, opaque fibers and regenerative fibers was less in ADMD. ADMD was classified into two groups; complete and incomplete adhalin-deficient. There was no essential difference between the two groups in clinical features and muscle histology, but the former was characterized by more severe clinical features than the latter. ADMD can be caused by various types of mutations in the adhalin gene.

Adolescent↗
PubMed1997

Isonymy structure of Sucre and Táchira, two Venezuelan states.

The isonymy structure of two Venezuelan states, Sucre and Táchira, is described using the surnames of the Register of Electors updated in 1991. The frequency distribution of surnames pooled together by sex was obtained for the 57 counties of Sucre and the 52 counties of Táchira, based on total population sizes of 158,705 and 160,690 individuals, respectively. The coefficient of consanguinity resulting from random isonymy (phi ii), Karlin and McGregor's ni (identical to v), and the proportion of the population included in surnames represented only once (estimator A) and in the seven most frequent surnames (estimator B) were calculated for each county. RST, a measure of microdifferentiation, was estimated for each state. The Euclidean distance between pairs of counties within states was calculated together with the corresponding geographic distances. The correlations between their logarithmic transformations were significant in both cases, indicating differentiation of surnames by distance. Dendrograms based on the Euclidean distance matrix were constructed. From them a first approximation of the effect of internal migration within states was obtained. Ninety-six percent of the coefficient of consanguinity resulting from random isonymy is determined by the proportion of the population included in the seven most frequent surnames, whereas between 72% and 88% of Karlin and McGregor's ni for Sucre and Táchira, respectively, is determined by the proportion of population included in surnames represented only once. Surnames with generalized and with focal distribution were identified for both states, to be used as possible indicators of the geographic origin of their carriers. Our results indicate that Táchira's counties, on average, tend to be more isolated than Sucre's counties, as measured by RST, estimator B, and phi ii. Comparisons with the results obtained for other. Venezuelan states and other non-Venezuelan populations are also given.

Emigration and Immigration↗
PubMed1998

Sibs with Ritscher-Schinzel (3C) syndrome and anal malformations.

Ritscher-Schinzel syndrome (cranio-cerebello-cardiac syndrome, 3C syndrome) is a recently delineated disorder with Dandy-Walker malformation, congenital heart defects, and characteristic face. Various other defects, including eye and kidney malformations, have been described in the few patients reported. Here we describe 3 sibs born to consanguineous Pakistani parents with 3C syndrome. All 3 children had atrial septal defects II and ventricular septal defects and died within 3 months. Two of them had a Dandy-Walker malformation, whereas 1 had only slightly dilated ventricles. One sib had anal atresia, and another a ventrally displaced anus. The findings in the 3 sibs demonstrate the intrafamilial variation in the Ritscher-Schinzel syndrome, because the second sib did not have a Dandy-Walker malformation. Anal anomalies have not been previously reported as a component manifestation of the disorder. The occurrence of 3 affected sibs in a consanguineous family confirms autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed1998

Recognizable inherited syndrome of progressive central nervous system degeneration and generalized intracranial calcification with overlapping phenotype of the syndrome of Aicardi and Goutières.

Five boys and two girls from a large consanguineous British Muslim family of Pakistani origin are described. All presented from infancy to early childhood with progressive moderate to severe developmental delay, postnatal microcephaly, spastic quadriplegia, refractory seizures, and visual handicap. Cerebrospinal fluid (CSF) pleocytosis was present in three children. Neuroimaging with computerized tomography on three boys and a girl showed generalized cortical atrophy, dilatation of the lateral, third, and fourth ventricles, widening of the surface CSF spaces, hypoplasia of the posterior fossa structures, and multiple and solitary calcifications in the cerebral cortex and punctate calcifications involving basal ganglia, cerebellum, and the Sylvian fissure. Histopathological examination of the brain from three boys and one girl confirmed generalized cortical and cerebellar atrophy with widespread calcifications within the cortical grey and white matter, the basal ganglia, the cerebellum, and in some areas along the capillaries. Investigations excluded a possible nongenetic cause. Parental consanguinity favor autosomal recessive inheritance. This appears to be a recognizable syndrome overlapping the syndrome of Aicardi and Goutières (MIM 225750).

Basal Ganglia Diseases↗
PubMed1997

[Genetic structure of the population of Guarico, Venezuela, studied through isonymy].

The genetic structure of the State of Guárico, Venezuela, was studied through the distribution of surnames from individuals above 40 years of age, obtained from the register of electors. The sample studied consisted in 109,200 individuals and 14,138 different surnames. For each of the 32 counties of the State, the following estimators were calculated: percentage of the population included in surnames which appear only once (estimator A), percentage of the population included in the seven most frequent surnames (estimator B), the coefficient of consanguinity due to random isonymy (n phi ii), and Karlin and McGregors ni nu, an estimator of migration. The correlation between n phi ii and B was 0.97, indicating that 94% of the variation observed in the coefficient of consanguinity due to random isonymy is due to the seven most frequent surnames. The correlation between A and ni was 0.93, so that 86% of the variation observed in ni, is due to surnames which appear only once. On the other hand, correlations between A and B, and between n phi ii and nu were non significant (0.25 and 0.01 respectively), meaning that they are measuring different features of population structure: B and n phi ii, and v were non significant (0.25 and 0.01 respectively), meaning that they are measuring different features of population structure: B and n phi ii, isolation, and A and nu, migration. The most isolated counties of Guárico, according to n phi ii and B, are Santa Rita, Espino, El Calvario, Ortiz and Santa María de Ipire. Microdifferentiation of the State was studied through the estimation of RST, which gave a value of 0.0008. Comparing this value with those obtained in other Venezuelan States, it is found that Guárico, with Aragua and Yaracuy, are among the least differentiated States, probably because of the absence of important geographical barriers and the nearness to the Capital City of our country.

Adult↗
PubMed1998

Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature.

Microcephalic and osteodysplastic primordial dwarfism (MODP) types I, II, and III were defined by Majewski et al. in 1982. This group of syndromes was characterized by intrauterine growth retardation, microcephaly, and typical facial appearance with prominent nose and micrognathia. Type II was clearly different, both clinically and radiologically, whereas types I and III shared manifestations. Distinction between the latter two was established on the basis of subtle radiological differences. In 1967, Taybi and Linder described another syndrome with microcephalic congenital dwarfism. There is a consensus that MODP type I and III and Taybi-Linder cephaloskeletal dysplasia represent the same disorder. We report on four patients with MODP type Taybi-Linder syndromes, two of whom were born to unrelated but consanguineous parents, while the other two were sibs. Second-trimester prenatal detection by ultrasonography was possible in one case. Consanguinity in two cases and recurrence among sibs are consistent with autosomal recessive inheritance.

Abnormalities, Multiple↗
PubMed1998

[An epidemiological study of the thrombocytopenia with radial aplasia syndrome (TAR) in Spain].

OBJECTIVE: There are numerous published papers on TAR syndrome. Nevertheless, most of them refer to cases or families with several affected members, but we could find no publication epidemiologically analyzing a consecutive series of cases. PATIENTS AND METHODS: We show the characteristics of the six cases with TAR syndrome identified in the consecutive series of 25,967 malformed live born infants detected among 1,431,368 live births surveyed by the ECEMC (Spanish Collaborative Study of Congenital Malformations) since April 1976 until June 1997. RESULTS: The minimal estimated frequency of TAR syndrome in our area is 0.42 per 100,000 live born infants, with a confidence interval of 0.15 to 0.91. There was no known consanguinity among the cases' parents, nor other affected family members. The sex ratio was 1:1. Although it is generally considered that the syndrome is autosomal recessive, genetic heterogeneity cannot be ruled out. CONCLUSIONS: Our cases concur with published data with respect to the low frequency of consanguineous parents. However we did not find a higher proportion of girls affected as has been described previously.

Abnormalities, Multiple↗
PubMed2025

Exome sequencing identifies a homozygous splice site variant in RP1 as the underlying cause of autosomal recessive retinitis pigmentosa in a Pakistani family.

BACKGROUND: Mutations in RP1 gene are the third leading cause of inherited retinal dystrophies (IRDs) in Pakistani families. PATIENTS: A two-generation consanguineous Pakistani family underwent both clinical and genetic analyses. Clinical examinations included visual acuity test, visual field, fundoscopy, and ocular coherence tomography (OCT). Whole exome sequencing (WES) was performed on the proband's DNA, and Sanger sequencing was performed to validate the WES findings. Splicing prediction tools such as Human Splicing Finder (HSF), NNSplice predictor, SpliceAI, MaxENTScan, and SpliceRover were used. RESULTS: A nuclear family of seven children, comprising five affected individuals (four males and one female) and two healthy siblings, was recruited from northwestern Pakistan. The proband was a 49-years old male who was presented with complaints of decreased visual acuity and night blindness since early childhood. Upon clinical evaluation, the proband appeared to have severely reduced visual acuity of hand movement (HM), bilateral visual field constriction, a waxy pale disc with vascular attenuation, pigmentary bone spicules at the periphery associated with chorioretinal degeneration, diffuse macular atrophy, and horizontal nystagmus in both of his eyes. Exome sequencing (ES) in the proband identified a homozygous splice site variant (NM_006269.2: c.615 + 1G > A) in RP1 gene. In-silico analysis, genotype-phenotype co-segregation study, and literature survey strongly supported the causality of the detected variant. CONCLUSIONS: We report a previously known pathogenic splice site variant of RP1 as the underlying cause of early-onset autosomal recessive retinitis pigmentosa (arRP) in a Pakistani family. We contemplate that the detected allele might constitute a mutational hotspot in RP1.

Humans↗
PubMed2004

Harlequin fetus.

We report a case of harlequin fetus born to the consanguineous parents. She had the typical skin manifestations of thick armour like scales with fissures, complete ectropion and eclabium, atrophic and crumpled ears and swollen extremities with gangrenous digits. Supportive treatment was given but the neonate died on the 4th day.

Consanguinity↗
PubMed2003

Pendred's syndrome.

This report describes Pendred's syndrome in three siblings of a consanguineous marriage, belonging to Rahim YarKhan. The children presented with deafmutism and goiters. The investigations included scintigram, perchlorate discharge test and audiometery. The perchlorate discharge was positive in index case. Bilateral sensorineural hearing defect was detected on Pure Tone Average (PTA) audiometry. Meticulous clinical and laboratory evaluation is mandatory for the detection of rare disorders like Pendred's syndrome.

Child↗
PubMed2003

Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation.

BACKGROUND: The syndrome of congenital myasthenia with episodic apnea (CMS-EA) was previously found to be due to mutations in the choline acetyltransferase gene (CHAT). OBJECTIVE: To identify the mutations underlying CMS-EA in a Turkish multiplex family. DESIGN: Direct sequencing of the CHAT gene. PATIENTS: A consanguineous Turkish family with 2 siblings affected by muscular weakness and episodic respiratory distress. RESULTS: The sequencing of CHAT coding exons identified a previously unknown missense mutation that affected a highly conserved amino acid residue (I336T). The mutation was absent in 164 control chromosomes. CONCLUSIONS: The high degree of conservation in different species strongly suggests that I336T is a functionally important amino acid residue. The absence of I336T from a large control sample further supports the pathogenic role of I336T in CMS-EA. This is the second report of CHAT mutations causing presynaptic CMS.

Adult↗
PubMed2006

Phenotypic variability among adult siblings with Sjögren-Larsson syndrome.

BACKGROUND: Sjögren-Larsson syndrome (SLS) is an early childhood-onset disorder with ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy caused by the deficiency of fatty aldehyde dehydrogenase due to mutations in the ALDH3A2 gene (the gene that encodes microsomal fatty aldehyde dehydrogenase). Cerebral proton magnetic resonance spectroscopy in those with SLS demonstrates an abnormal white matter peak at 1.3 ppm, consistent with long-chain fatty alcohol accumulation. OBJECTIVE: To define the clinical course and proton magnetic resonance spectroscopic findings of SLS in adults. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS: Six siblings of a consanguineous Arab family with early childhood-onset SLS who carry the 682C-->T mutation in the ALDH3A2 gene were reinvestigated in adulthood. RESULTS: The 6 affected siblings ranged in age from 16 to 36 years. All exhibited the typical clinical and imaging manifestations of SLS, but their severity markedly varied. Neurological involvement was apparently nonprogressive, and its severity showed no correlation with age. Cerebral proton magnetic resonance spectroscopy showed a lipid peak at 1.3 ppm, with decreasing intensity in the older siblings. CONCLUSION: These observations document significant clinical variability and the nonprogressive neurological course of SLS in adult siblings with the same ALDH3A2 genotype, and demonstrate possible correlation of proton magnetic resonance spectroscopic changes with age, suggesting unknown pathogenic mechanisms to compensate for the responsible biochemical defect in this disease.

Adolescent↗
PubMed2005

Genotype-phenotype correlation in 2 Indian families with severe granular corneal dystrophy.

OBJECTIVES: To determine genotypes in 2 Indian families with severe granular corneal dystrophy, to document clinical and histopathologic features, and to attempt a genotype-phenotype correlation. METHODS: Mutation analysis of exon 12 of the TGFBI gene was carried out in 9 individuals from 2 families. RESULTS: A C-->T mutation at residue 1710 of TGFBI complementary DNA, corresponding to an Arg555Trp mutation in keratoepithelin, was found in affected members of both families. In 5 patients, this mutation was homozygous, and it was heterozygous in the other 4. Clinical examination revealed a severe form of granular corneal dystrophy with early onset and superficial lesions in the homozygous individuals and a milder phenotype in the heterozygous individuals. Histopathologic evaluation of corneal specimens from 2 homozygous patients confirmed the presence of superficial granular deposits. CONCLUSIONS: To our knowledge, this is the first molecular and clinical characterization of severe granular corneal dystrophy in India. Genotype-phenotype correlation and comparison with earlier reports on this entity highlight the uniform expressivity of the Arg555Trp allele in homozygous individuals. CLINICAL RELEVANCE: Homozygous granular corneal dystrophy has a severe phenotype and can be recognized based on clinical and histopathologic features, especially in association with consanguinity or inbreeding.

Adolescent↗
PubMed2005

Clinical and molecular characterization of a family with autosomal recessive cornea plana.

BACKGROUND: Autosomal recessive cornea plana is characterized by a flattened corneal surface associated with hyperopia and various anterior segment abnormalities. Mutations have been detected in the keratocan gene (KERA), a member of the small leucine-rich proteoglycan family. OBJECTIVE: To clinically and molecularly characterize a consanguineous family of Hispanic origin in which 3 individuals are affected with cornea plana. METHODS: Clinical ophthalmic examination, including corneal topography and axial eye length measurement, was performed on 7 family members. Molecular analysis of KERA was performed on DNA from each family member who had been examined. RESULTS: All 3 affected individuals showed extreme flattening of the cornea (< 36 diopters [D]), normal axial eye lengths, and hyperopia greater than 6.25 D (spherical equivalent). Anterior segment abnormalities included scleralization of the cornea and central iris strands to the corneal endothelium. Affected individuals were homozygous for a novel mutation in KERA. The sequence change was found in exon 2, which results in an asparagine to aspartic acid change at codon 131. This amino acid change occurs within a highly conserved leucine-rich repeat of keratocan. CONCLUSIONS: The cause of disease in this family is likely to be a mutation in exon 2 of KERA. Other mutations in KERA known to cause cornea plana also fall within the region encoding the leucine-rich repeat motifs and are predicted to affect the tertiary structure of the protein. CLINICAL RELEVANCE: This is the first report of the identification of a mutation within KERA in a family of Hispanic origin with autosomal recessive cornea plana. Although the vast majority of cases of cornea plana are in individuals of Finnish descent, this report demonstrates the occurrence of the disease in other populations.

Amino Acid Sequence↗
PubMed1989

Autosomal recessive nonsyndromal profound childhood deafness in a large pedigree. Audiometric features of the affected persons and the obligate carriers.

Nonsyndromal autosomal recessive profound childhood deafness will affect about one in 4000 children in western Europe. A nonsyndromal autosomal recessive type of profound childhood deafness was thought to be the cause of deafness in at least eight and probably 12 children from a large family with various consanguineous matings and other family interrelations. Audiograms of all affected deaf children showed a profound childhood deafness with only a very slight variation. Audiometric examinations, such as pure-tone audiometry, high-frequency audiometry, stapedial reflexes, and Bekesy audiometry, of ten obligate or presumed carriers did not show any significant findings that would allow identification of carriers of this autosomal recessive gene. Families like this one seem to be very rare. Large clinically well-studied families like this one are indispensable for gene linkage studies of nonsyndromal autosomal recessive types of profound childhood deafness. Such studies should make it possible to trace the origin of these types of childhood deafness at an early age. In consequence, carrier detection should also become available.

Adult↗
PubMed1976

Familial imperforate anus.

A boy, 2 years 5 months of age, was admitted for examination and was found to be mentally retarded. He had a history of low birth weight, covered anus, and perineal fistula. Investigation revealed ventricular septal defect and persistent left superior vena cava, left upper lobe atelectasis, hand and foot anomalies, agenesis or nonfunctioning right kidney and large left kidney with double pelves and double ureters, and large sigmoid colon. Family history revealed consanguineous parents and a mentally retarded elder sister who had anorectal atresia with introital fistula and perineal ectopic stenotic anus. This family demonstrates two extremes of the same syndrome, most probably inherited as an autosomal-recessive entity.

Abnormalities, Multiple↗
PubMed1977

Propionic acidemia and anorectal anomalies in three siblings.

Three siblings suffering from recurrent vomiting, hypotonia, hyperpnea, dehydration, and ketoacidosis were diagnosed as having ketotic hyperglycinemia secondary to propionic acidemia. They also had leukopenia and thrombocytopenia, and two of them had anorectal malformations, one an imperforate anus with rectoperineal fistula, and the other an ectopic anus. The occurrence of propionic acidemia and anorectal anomalies in three siblings out of eight children in a consanguineous marriage suggests an autosomal recessive genetic inheritance.

Amino Acid Metabolism, Inborn Errors↗