Activity of NADH- and NADPH-dependent methemoglobin reductases in erythrocytes from fetal to adult age

Summary The activities of NADH- and NADPH-dependent methemoglobin reductases were investigated in 22 fetuses between the 12th and 24th week of pregnancy and in eight age groups including premature and newborn babies and adults. Each blood sample was assayed simultaneously for both activities. NADH-methemoglobin reductase (MR) appears to be diminished in erythrocytes of premature and newborn babies. Infants below the 6th week of life also show significantly lower values than those observed in adults. Between 7 weeks and 6 months of life NADH-MR activity reaches values comparable to those of the adults. — NADPH activity in the erythrocytes of premature babies, newborns and infants is significantly higher than in older children and adults. Prior to the 18th week of gestation fetuses show NADH-MR levels lower than the older ones. NADH-MR values in fetuses between the 18th and 24th week of gestation are not different from those measured in premature babies. The NADPH-MR activity also appears to be significantly lower in fetuses of less than 19 weeks of intrauterine life in comparison with the older ones. Moreover, NADPH-MR activity in fetuses between the 19th and 24th week is lower than in prematures and newborns.The possibility that low NADH-MR values in fetuses (30% as compared to adults) in the first 5 months of pregnancy could predispose to intrauterine methemoglobinemia has to be carefully evaluated when toxic drugs are prescribed to the mother.—Moreover, the still lower NADH-MR levels that might be expected in fetuses homozygous or heterozygous for NADH-MR deficiency may be a cause for the frequent occurrence of mental retardation in families with hereditary methemoglobinemia.     

De novo simultaneous reciprocal translocation and deletion.

A female infant with severe mental retardation, general hypotonicity, and a history of generalised oedema, cyanosis, heart murmur, and nystagmus in the first days of life was found to have both a translocation and a deletion. Her karyotype was 46,XX,del(21)t(18;21)(18p ter leads to 18q11::21q21 leads to 21qter;21pter leads to 21q11::18q11 leads to 18q ter). The karyotype of both parents was normal. The proposita is the result of a three break point exchange and is monosomic for part of the dark band q11 q21 of chromosome 21. It is suggested that in cases with mental retardation and apparent balanced de novo reciprocal translocation a small undetected deletion in one of the chromosomes involved in the translocation could explain the mental retardation.     

Congenital methemoglobinemia: a rare case of cyanosis in the newborn

We report the case of a newborn presenting a cyanosis after the birth with a good general state. Congenital methemoglobinemia is a rare disease which is characterized by a brutal appearance, in early infancy, of a bluish skin color not regressing with oxygen inspiration, and by a good general state. It is due to the recessive autosomal NADH-cytochrome b5 reductase (EC. 1.6.2.2) deficiency. This enzyme normally allows the reduction of the physiologically formed methemoglobinemia. Two forms of congenital methemoglobinemia have to be distinguished: the benign form (type I) and the severe form (type II).     

NADH-cytochrome b5 reductase in a Turkish family with recessive congenital methaemoglobinaemia type I

The development of cyanosis at birth, the so-called blue baby syndrome, alerts paediatricians to the presence of congenital heart disease. In rare cases where the arterial blood gas analysis is normal the cyanosis is a consequence of methaemoglobinaemia. There are three distinct origins of methaemoglobinaemia; the presence of a haemoglobin variant, environmental toxicity and deficiency of cytochrome b5 reductase (cb(5)r). Two children born to two sets of first-degree related parents were cyanotic from birth. Differential diagnosis eliminated cardiac and pulmonary abnormalities. Measurement of methaemoglobin levels confirmed recessive congenital methaemoglobinaemia (RCM) and treatment with ascorbic acid was commenced. In the absence of neurological defects, type I disease was diagnosed. Sequence analysis of CYB5R3 revealed two different missense mutations (one which is novel, Ile85Ser) in the two families. Neither of the mutations was located in the FAD or the NADH binding sites of cb(5)r, thus supporting a diagnosis of type I disease.     

The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia

Hemoglobin M (HbM) is a group of abnormal hemoglobin variants that form methemoglobin, which leads to cyanosis and hemolytic anemia. HbM-Milwaukee-2 is a rare variant caused by the point mutation CAC>TAC on codon 93 of the hemoglobin subunit beta (HBB) gene, resulting in the replacement of histidine by tyrosine. We here report the first Korean family with HbM-Milwaukee-2, whose diagnosis was confirmed by gene sequencing. A high index of suspicion for this rare Hb variant is necessary in a patient presenting with cyanosis since childhood, along with methemoglobinemia and a family history of cyanosis.     

Cataract, hypertrichosis, and mental retardation (CAHMR): a new autosomal recessive syndrome.

We have studied 2 Egyptian sibs (the offspring of normal first cousins) with congenital cataract, hypertrichosis, mental retardation, and normal chromosomes. Review showed that the condition of our patients was not similar to any previously reported entity. POSSUM lists 84 syndromes with any of the above 3 main traits. Two disorders with cataract and mental retardation, Martsolf syndrome and Mollica-Pavone-Anterer syndrome, have overlapping manifestations and therefore are particularly differentiated from our cases. We suggest that the association of congenital cataract, hypertrichosis, and mental retardation observed in this report represents a new autosomal recessive syndrome.     

Occurrence of the alpha thalassaemia-mental retardation syndrome (non-deletional type) in an Australian male.

The rare association of alpha thalassaemia and mental retardation has been described previously. Molecular studies of the alpha globin cluster in these cases have been heterogeneous, with some patients having large deletions while in others the alpha globin complex appears to be intact (non-deletional). The non-deletional cases form a distinct group whose features include severe mental retardation, haematological changes of haemoglobin H (Hb H) disease, developmental defects, and unusual patterns of inheritance. To date, five cases have been described with non-deletional alpha thalassaemia-mental retardation. We present here a further example of a young male of Northern European origin who appears to have the non-deletional form of the disease. Clinical features included severe mental retardation, Hb H disease, and developmental defects similar to those reported previously. DNA mapping, including pulsed field electrophoresis, showed no evidence of deletions within the alpha globin cluster. Karyotypic analysis indicated an increase in random breakage, which has been observed previously in one case of deletional alpha thalassaemia-mental retardation. Profuse Hb H bodies and Hb H on electrophoresis were consistent with Hb H disease. However, the latter was present at a relatively low level (1.6%) and, as well, the mean corpuscular volume (82.8 fl) and mean corpuscular haemoglobin (26.4 pg) were surprisingly high. Our findings are compared to other cases described with the non-deletional Hb H-mental retardation syndrome.     

Identification of three patients with a very mild form of Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by mental retardation, congenital anomalies, and growth deficiency. The syndrome is caused by a block in cholesterol biosynthesis at the level of 7-dehydrocholesterol reductase (7-DHCR), which results in elevated levels of the cholesterol precursor 7-dehydrocholesterol (7-DHC) and its isomer 8-dehydrocholesterol (8-DHC). We report on three patients from two families with a very mild clinical presentation of SLOS. Their plasma cholesterol values were normal and their plasma levels of 7- and 8- DHC were only slightly elevated. In cultured skin fibroblasts, a significant residual 7-DHCR activity was found. All three patients were compound heterozygotes for a novel mutation affecting translation initiation (M1L). Two of them had the common IVS8-1G>C null mutation and the third patient an E448K mutation in the 7-DHCR gene. Our findings emphasize the importance of using a sensitive method for measuring precursors of cholesterol in combination with mutation analysis to analyze patients with only minimal clinical SLOS-like signs.     

The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.     

Duchenne muscular dystrophy with adrenal insufficiency and glycerol kinase deficiency: high resolution cytogenetic analysis with molecular, biochemical, and clinical studies.

A syndrome of Duchenne muscular dystrophy (DMD), adrenal hypoplasia, glycerol kinase deficiency, and mental retardation has been recognised. We report a further case ascertained from a history of DMD, severe mental retardation, and an Addison-like disorder. Cytogenetic analysis of the proband revealed an interstitial deletion of the short arm of the X chromosome. from Xp21.1 to Xp22.11, comprising about 9% of the length of the normal X chromosome. His mother was heterozygous for the deletion, but his maternal grandmother and sister both had two normal X chromosomes. DNA probe analysis confirmed the existence of a deletion in the affected boy, as probes 754, C7, XJ1-1, and pERT87 consistently failed to hybridize to his DNA. His sister was heterozygous for the RFLP associated with 754, thus confirming that she had two normal X chromosomes. There was no evidence of chronic granulomatous disease, other immunological defect, or retinitis pigmentosa in this case. Biochemical studies revealed gross glyceroluria and hyperglycerolaemia, indicating glycerol kinase deficiency which has been confirmed enzymatically. We have subsequently screened 21 other boys with DMD for glyceroluria and found one other case. Cytogenetic analysis has also been performed in nine other families, where a boy with DMD has been shown to have a deletion of DNA sequences localised to the region Xp21. None of these cases demonstrated any cytogenetic abnormality, nor has their clinical course been unusual.     

133例智力低下患儿细胞遗传学研究

目的探讨智力低下患儿与染色体异常的关系。方法常规外周血染色体核型分析。结果 133例患儿中共检出染色体异常74例,异常检出率55.6%。其中常染色体数目异常62例,结构异常9例;性染色体数目异常2例,结构异常1例,结论染色体异常是导致儿童智力低下的重要原因,对此类患儿进行染色体核型分析很有必要。     

Smith-Lemli-Opitz syndrome in female, monozygotic twins

A pair of monozygotic female twins with SLO syndrome is presented. We have found only one paper in the literature that referred to twins with this rare syndrome. The multiple congenital defects in these cases, consist of limb and genital abnormalities, retardation of growth, mental deficiency, craniofacial defects and abnormal neurological status.     

Familial congenital laryngeal abductor paralysis: different expression in a family with one male and three females affected.

A brother and two sisters of remotely consanguineous parents had congenital laryngeal abductor paralysis and moderate mental retardation. In the two older sibs, mental deficiency could have resulted from birth asphyxia, but the youngest girl was already microcephalic at birth and had no apparent asphyxia. The mother, who was healthy and of normal intelligence, was found on laryngoscopy to have unilateral laryngeal abductor paralysis. This is the first family with both mentally retarded and nonretarded affected members with congenital laryngeal abductor paralysis. Inheritance is most likely autosomal dominant with variable expression, but autosomal recessive inheritance, with both parents carriers and the mother an affected homozygote, and X linked inheritance are also possible.     

X linked mental retardation with non-deletional alpha thalassaemia (ATR-X): further delineation of the phenotype.

Two sibs with non-deletional alpha thalassaemia and mental retardation (ATR-X) have been ascertained showing variable neurological features. The proband had a complex neurological picture with recurrent apnoea, complex partial seizures, and prolonged periods of semiconsciousness between 12 and 17 months of age. Episodes of spontaneous laughter were also a feature. An EEG was initially normal. Hb H inclusions were present but rare in this family. The sole genital anomaly was deficiency of the foreskin, a feature not previously described in ATR-X.     

A new X-linked multiple congenital anomalies/ mental retardation syndrome

We report on 2 boys, the sons of sisters, and their mother's brother who have a new, X-linked multiple congenital anomalies/mental retardation (MCA/MR) syndrome. The propositus was a 16-month-old caucasian male with 1)mental retardation, 2) congenital microcephaly, 3)postnatal growth deficiency, 4)ridged metopic suture with narrow bifrontal diameter, 5)upslanted palpebral fissures with persistent epicanthal folds, strabismus, and lacrimal duct obstruction, 6)narrow palate, 7)macrodontia, 8)anteverted ears, 9)atrial septal defect, 10)dry brittle scalp hair and 11)cutis marmorata. His chromosomes were normal. His cousin and uncle were similarly affected. This distinctive MCA/MR syndrome is added to the list of X-linked malformation syndromes known at the present time.     

Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India

We report the clinical features and molecular characterization of 23 patients with cyanosis due to NADH‐cytochrome b5 reductase (NADH‐CYB5R) deficiency from India. The patients with type I recessive congenital methemoglobinemia (RCM) presented with mild to severe cyanosis only whereas patients with type II RCM had cyanosis associated with severe neurological impairment. Thirteen mutations were identified which included 11 missense mutations causing single amino acid changes (p.Arg49Trp, p.Arg58Gln, p.Pro145Ser, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, p.Ala179Thr, p.Thr238Met, and p.Val253Met), one stop codon mutation (p.Trp236X) and one splice‐site mutation (p.Gly76Ser). Seven of these mutations (p.Arg50Trp, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, and p.Thr238Met) were novel. Two mutations (p.Gly76Ser and p.Trp236X) were identified for the first time in the homozygous state globally causing type II RCM. We used the three‐dimensional (3D) structure of human erythrocyte NADH‐CYB5R to evaluate the protein structural context of the affected residues. Our data provides a rationale for the observed enzyme deficiency and contributes to a better understanding of the genotype–phenotype correlation in NADH‐CYB5R deficiency.     

The CFC syndrome--report of the first two cases outside the United States

We report on two additional patients with the cardiofaciocutaneous (CFC) syndrome, the first to be reported outside the United States. They have several of the characteristic manifestations of this new multiple congenital anomalies/mental retardation syndrome, namely, mental retardation, growth retardation, relative macrocephaly, unusual face, abnormal hair, skin involvement, heart defect, hernias, and splenomegaly. Similar to all previously reported cases, these also were sporadic and had normal chromosomes.     

The CFC syndrome—report of the first two cases outside the United States

We report on two additional patients with the cardiofaciocutaneous (CFC) syndrome, the first to be reported outside the United States. They have several of the characteristic manifestations of this new multiple congenital anomalies/mental retardation syndrome, namely, mental retardation, growth retardation, relative macrocephaly, unusual face, abnormal hair, skin involvement, heart defect, hernias, and splenomegaly. Similar to all previously reported cases, these also were sporadic and had normal chromosomes.     

Ring chromosome 12 with variable phenotypic features: clinical report and review of the literature

A ring chromosome 12 (p13; q24.33) was observed in all cells analyzed from peripheral blood lymphocytes of a 15-year-old female referred for academic difficulties and growth delay. In addition to clinical manifestations generally observed with ring chromosome 12 such as growth retardation, mental deficiency, microcephaly, the patient had bilateral pseudocamptodactyly of little fingers, mild hirsutism, exaggerated lumbar lordosis, and ostium secundum atrial septal defect (ASD). The clinical features of reported cases are analyzed. The only consistent features were growth retardation and mental deficiency. Breakpoint in all the cases has been at the telomeric region with minimal deletion of chromosomal material. An account of complex changes at mitosis and meiosis in ring chromosome has been given. Examination of 200 metaphases demonstrated 2% cell line was showing 45,XX, -12. Serum lactate dehydrogenase (LDH) level was normal ruling out overlapping monosomy 12 syndrome.     

合肥地区110例染色体异常核型临床分析

目的探讨智力障碍、闭经、不良生育史、异常性征的病因。方法采取外周血进行细胞培养,染色体G带分析。结果1488例受检者有110例异常核型。结论染色体异常是智力障碍、闭经、不良生育史和性征异常的重要病因之一,染色体核型分析可为这类疾病的诊断和治疗提供有效的和重要的依据。