[Somatic comorbidity in children and adults with intellectual disability and mental health problems.] / Somatische comorbiditeit bij kinderen en volwassenen met een verstandelijke beperking en een psychiatrische aandoening.

BACKGROUND: People with intellectual disability (id) frequently suffer from somatic and psychiatric comorbidity. Somatic morbidity can be the cause and the result of mental health problems. Timely diagnosis and interdisciplinary management are essential for optimal health, development and quality of life.
AIM: To improve interdisciplinary cooperation of professionals involved in care for patients with id, with emphasis on prevalence, diagnosis, and treatment of somatic comorbidity.
METHOD: Literature review and expert opinion.
RESULTS: Epidemiology, diagnostics, and treatment of somatic comorbidity in patients with id are discussed. Additionally, roles and responsibilities of involved professionals are addressed.
CONCLUSION: Somatic comorbidity is highly prevalent in patients with id. People with id should be regularly screened for somatic comorbidity, and re-evaluated in case of behavioral changes. Where available, an id physician can be included in the interdisciplinary care team.

Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure.

A Saudi Arabian family presented with adult onset autosomal dominant progressive external ophthalmoplegia (adPEO) complicated by late onset reversible failure of the CNS, respiratory, hepatic, and endocrine systems. Clinical findings were suggestive of mitochondrial dysfunction and multiple mitochondrial DNA deletions were demonstrated on long range and real time polymerase chain reaction assays but not on Southern blotting. The disorder is caused by a novel heterozygous PEO1 mutation predicting a Leu360Gly substitution in the twinkle protein. The peculiar clinical presentation expands the variable phenotype observed in adPEO and Twinkle gene mutations.

Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics.

Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients.

POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.

OBJECTIVE: To identify POLG mutations in patients with sensory ataxia and CNS features. METHODS: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long-range PCR. RESULTS: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families. CONCLUSIONS: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.

Patient homozygous for a recessive POLG mutation presents with features of MERRF.

Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.

Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.

Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.

Infantile demyelinating neuropathy associated with a de novo point mutation on Ser72 in PMP22 and basal lamina onion bulbs in skin biopsy.

Codon 72 has been designated as a hot spot for distinct missense mutations in the peripheral myelin protein 22 (PMP22) gene. Ser72Leu substitution was associated with Dejerine-Sottas syndrome (DSS) in four patients and with congenital hypomyelination neuropathy (CHN) in one patient. Our objective was to report one other DSS patient with Ser72Leu substitution in PMP22 and to concurrently illustrate how less invasive procedures such as skin biopsy could provide a rapid and reliable alternative to conventional sural nerve biopsy for the characterization of histophenotypic features. A skin biopsy was carried out in a 2 4/12-year-old girl with muscle atrophy, hypotonia and weakness, as well as generalized areflexia and absent sensory and motor nerve responses. Standard electron microscope techniques were used. PMP22 was screened by automated direct nucleotide sequencing analysis. Morphological examination revealed basal lamina onion bulbs surrounding a de- or hypomyelinated axon in all nerve bundles. Mutation analysis demonstrated a missense point mutation in codon 72 of the PMP22 gene leading to a Ser72Leu substitution. Further genotype-phenotype correlations will have to determine whether morphologically distinct phenotypes can be correlated with specific mutations. For this purpose, cutaneous nerve bundles could serve as an alternative tool to help identify and classify subtypes in this heterogeneous syndrome.

Novel syndromic form of X-linked complicated spastic paraplegia.

This study presents a family with a syndromic form of X-linked mental retardation in which four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia. Multipoint linkage analysis with 24 highly polymorphic markers indicated two possible candidate regions: Xp21.1-Xq21.3 (flanking markers DXS1214 and DXS990) and Xq23-Xq27.1 (flanking markers DXS8020 and DXS984). The two known loci for X-linked mental retardation and spastic paraplegia are excluded: proteolipid protein in Xp21 and L1 cell adhesion molecule in Xq28. Therefore, the syndrome in this family appears to represent a previously undescribed X-linked spastic paraplegia-mental retardation syndrome.

Severe short stature, hyperphalangy of the index fingers, mental retardation and facial dysmorphism.

We present an adult female patient with a so far unreported syndrome of severe short stature, severe mental retardation, facial dysmorphism and hyperphalangy of the index fingers. Parental consanguinity suggests an autosomal recessive inheritance.

Zygodactyly as the most striking physical anomaly in an adult male patient with pure partial trisomy 1q.

We report on a dysmorphic and mentally retarded adult male patient with partial trisomy 1q resulting from a "de novo" tandem duplication of the 1q32.3-->q42 region. The dysmorphic features consisted of facial asymmetry, synophrys, right external strabismus, teeth anomalies and bilateral syndactyly of fingers III-IV and toes II-III evoking zygodactyly. Clinical comparison is made between the present observation and previously reported cases with pure duplication including the chromosome 1 segment (q32-->q42).

On a dominantly inherited myopathy with tubular aggregates.

A 19-year-old patient presented with exercise-related myalgia, fatigue and elevated creatine kinase levels. Histology of a muscle biopsy was characterized by the presence of very large amounts of tubular aggregates. Both his father and paternal grandfather had elevated creatine kinase and large amounts of tubular aggregates in their muscle biopsies. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with one to several smaller tubules. Disorders with tubular aggregates in the muscle fibres such as hyperornithinaemia with gyrate atrophy of the retina, hypokalaemic periodic paralysis, hyperkalaemic periodic paralysis, myotonia congenita, alcoholism, osteomalacic myopathy etc. have been excluded. Tubular aggregates can be found in muscle disorders characterized by exercise-induced cramps, pain and stiffness. They also represent the predominant histological feature of some familial myopathies due to a yet unidentified genetic defect. In our family, there was male-to-male transmission, confirming dominant inheritance.

Serum erythropoietin levels in elderly inpatients with anemia of chronic disorders and iron deficiency anemia.

OBJECTIVE: To analyze the relationship between serum erythropoietin levels and hemoglobin levels in elderly patients with anemia of chronic disorders related to cancer or acute infection when compared with anemic patients with iron deficiency. DESIGN: Prospective survey with comparison groups. SETTING: Tertiary care center. PATIENTS: An elderly group aged 70 and above (mean 84, range 70-96) was divided into subgroups of 45 with anemia of chronic disorders (23 with cancer and 22 with acute infection), 24 with iron-deficiency anemia, and 27 with no anemia. Thirty non-anemic younger adults were also studied. MEASUREMENTS: Serum erythropoietin (radioimmunoassay), complete blood count, serum iron, B12, folate and ferritin, liver and kidney function tests, blood gas analyses, and bacteriological and radiological tests. RESULTS: The serum erythropoietin levels were significantly lower in the elderly non-anemic hospitalized group than in the healthy younger group. A significant negative relationship between the log serum erythropoietin and hemoglobin levels was found in patients with iron deficiency, but not in the other groups. For any given hemoglobin level, the response of erythropoietin was significantly higher in anemic patients with iron deficiency when compared with the neoplastic and infectious group. CONCLUSION: Erythropoietin response to anemia is blunted in elderly patients with anemia of chronic disorders related to cancer or acute infection. Erythropoietin level is lower in non-anemic elderly inpatients than in healthy younger persons.

Effect of light on cell elongation, nucleic acid and protein synthesis in hypocotyls of Lupinus angustifolius.

The synthesis of DNA, RNA, protein and dry matter was followed in the elongating cells of hypocotyl of Lupinus (Lupinus angustifolius L.) germinating in total darkness or in continuous light. Light strongly inhibits the synthesis of DNA, RNA and protein. It was shown by histofluorometric DNA determinations that a reduced synthesis of DNA in continuous light is accompanied by a lower level of endomitosis in the cortex cells of the hypocotyl. In the dark cortex nuclei become 8 C while in the light they become only 4 C. The more pronounced differences between dark and light germinated hypocotyls of lupinus in comparison with pea epicotyls is explained to a great extent by mitotic growth.