Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease.

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]. This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis-inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy.

The Warburg micro syndrome (WARBM) is a genetically heterogeneous syndrome linked to at least 4 loci. At the clinical level, WARBM is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, severe mental retardation, and hypogonadism. In some families additional clinical features have been reported. The presence of uncommon clinical features (peripheral neuropathy, cardiomyopathy) may result in misdirected molecular diagnostics. Using the next generation sequencing approach (NGS), we were able to diagnose WARBM1 syndrome by detection of a new mutation within the RAB3GAP1 gene. We have detected some DNA variants which may be responsible for cardiomyopathy. We did not find any obvious pathogenic mutation within a set of genes known to be responsible for hereditary motor and sensory neuropathy (HMSN). We conclude that: (i) in clinically delineated syndromes, a classical single-gene oriented approach may be not conclusive especially in the presence of rare clinical features, (ii) peripheral neuropathy and cardiomyopathy are rare additional symptoms coexisting with WARBM1, (iii) a pleiotropic effect of a single point mutation is sufficient to be causative for WARBM1 and (iv) more WARBM-affected patients should be reported to delineate a complete phenotype.

Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis.

Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination - hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy.

Molecular and clinical consequences of novel mutations in the arylsulfatase A gene.

Metachromatic leukodystrophy (MLD), a severe neurodegenerative metabolic disorder, is caused by deficient activity of arylsulfatase A (ARSA; EC 3.1.6.8), which leads to a progressive demyelinating process in central and peripheral nervous systems. In this study, a DNA sequence analysis was performed on six Polish patients with different types of MLD. Six novel mutations were identified: one nonsense (p.R114X), three missense (p.G122C, p.G293C, p.C493F) and two frameshift mutations (g.445_446dupG and g.2590_2591dupC). Substitutions p.G293C and p.C493F and duplication g.445_446dupG caused a severe reduction of enzyme activity in transient transfection experiments on mammalian cells (less than 1% of wild-type (WT) ARSA activity). Duplication 2590_2591dupC preserved low-residual ARSA activity (10% of WT ARSA). In summary, the novel MLD-causing mutations in the exons 2, 5 and even in 8 of the ARSA gene described here can be classified as severe type 0, leading in homozygosity to the late infantile form MLD. Growth retardation, delayed motor development, gait disturbances, tonic-clonic seizures and non-epileptic muscle spasms were the first onset symptoms in patients with late infantile form of MLD. In individual with juvenile type MLD gait disturbances evidenced the onset of the disease, while in a patient with late juvenile MLD, difficulties at school were displayed.

Transferrin hypoglycosylation in hereditary fructose intolerance: using the clues and avoiding the pitfalls.

Hereditary fructose intolerance (HFI) is caused by a deficiency of aldolase B due to mutations of the ALDOB gene. The disease poses diagnostic problems because of unspecific clinical manifestations. We report three cases of HFI all of whom had a chronic disease with neurological, nephrological or gastroenterological symptoms, whereas nutritional fructose intolerance, the pathognomonic sign of HFI, was apparent only in retrospect. In all patients a hypoglycosylated pattern of transferrin isoforms was found but was misinterpreted as a sign of CDG Ix. The correct diagnosis was achieved with marked delay (26, 36 and 24 months, respectively) by sequencing of the ALDOB gene two common mutations were identified on both alleles or on one (A150P/A175D, A150P/-, and A150P/A175D). The diagnosis was further supported by normalization of transferrin isoforms on a fructose-free diet. Data available in two patients showed that following the fructose restriction the type I pattern of carbohydrate-deficient transferrin detectable on fructose-containing diet disappeared after 3-4 weeks. These cases illustrate that in the first years of life HFI may show misleading variability in clinical presentation and that protein glycosylation analysis such as transferrin isofocusing may give important diagnostic clues. However, care should be taken not to misinterpret the abnormal results as CDG Ix as well as to remember that a normal profile does not exclude HFI due to the possibility of spontaneous fructose restriction in the diet. The presented data also emphasize the usefulness of ALDOB mutation screening for diagnosis of HFI.

Ultrastructural study of mother and daughter muscle changes with mitochondrial encephalomyopathy.

We present the light and electron microscopy examinations of skeletal muscle biopsies from a 36-year-old mother and her 13-year-old daughter with mitochondrial encephalomyopathies. Clinical signs and symptoms suggesting mitochondrial disease, such as disseminated neurological symptoms, visual and hearing disturbances, mental disability, exercise intolerance, heart conduction disturbances, short stature, family history, were present in both patients. The mother's niece (8 years old) also died with progressive neurological disorder. CT showed cerebral and cerebellar atrophy in mother and multifocal subcortical atrophy in daughter. There was lactic acidosis in blood serum and cerebrospinal fluid in daughter. In the daughter's muscle a lot of fibres looked like ragged red fibres. Electron microscopic examination revealed the alterations of mitochondria in skeletal muscle of both patients that concerned the number, size, shape and the fine structural appearance of the mitochondria. The most characteristic mitochondrial abnormalities in daughter's muscles were paracrystalline inclusions in the intracristal space. In mother's muscles most of the mitochondria were markedly enlarged and they possessed aberrant configurations of cristae. The mitochondrial matrix contained sometimes spherical electron dense bodies different in size and vacuoles. Ring-shaped mitochondria were also observed. The most prominent ultrastructural feature, similarly as in daughter, was the occurrence of intramitochondrial highly ordered paracrystalline inclusions.

[Clinical picture of spinocerebellar ataxia type I (SCA1)]. / Obraz kliniczny bezladu rdzeniowo-mózdzkowego typu I (SCA1).

Spinocerebellar ataxia is a group of diseases with autosomal dominant inheritance heterogenous both clinically and genetically. So called dynamic mutations underlie most these nosological units. The clinical patterns of various SCA types have not yet been defined completely. The purpose of the present report was description of the typical symptoms and signs of type 1 SCA. Seventeen patients from 13 families (M-2, F-15) were studied clinically in detail. The diagnosis was confirmed by DNA analysis. The assessment included neurological status, cognitive functions, the results of EEG, EMG, SEP, VEP, BAER and MRI examinations. The pedigrees indicated autosomal dominant inheritance pattern. The mean age at onset was 35.5 +/- 6.8 years (range 23-45 years) and it suggested negative correlation with the number of CAG repetitions. Cerebellar syndrome limb and truncal, ataxia and dysarthria was present in all cases. Six patients had nystagmus, 3 had slow saccades, 2 had gaze limitation upward, and lateral and 6 had dysphagia. Signs of pyramidal system involvement were found in 10 cases, one had athetotic movements, one had orthostatic hypotension. Two patients had dementia features, 9 had some decline of intellectual functions, mainly with difficulties of memorization, learning and concentration. In 16 cases MRI demonstrated vermis atrophy and atrophy of cerebellar hemispheres, 14 had fourth ventricle dilatation, 8 had flattening of pons base, 8 had narrowing of cervical spinal cord, 8 had dilated CSF spaces over frontal lobes and in 6 cases lateral ventricles were dilated. Electrophysiological peripheral nervous system investigations showed in 16 cases long-standing damage to the motor and sensory peripheral neurons at the level of nerve trunks, more pronounced in sensory nerves. In 13 cases peripheral neuron damage was subclinical. SEP showed in all patients disturbed function of ascending sensory pathways at peripheral and spinocortical levels.

[Hyperactivity and behavioral disorders in Sanfilippo A (mucopolysaccharidosis type IIIA)--case report and review of the literature]. / Nadpobudliwosc psychoruchowa i zaburzenia behawioralne w przebiegu choroby Sanfilippo A (mukopolisacharydozy typu IIIA)--opis przypadku i przeglad pismiennictwa.

Sanfilippo syndrome is one of mucopolysaccharidoses. The main symptom of this syndrome is regression of psychomotor development and neurological signs which occur between 2 and 6 years old. Unlike other mucopolysaccharidoses body dysmorfic features are relatively rare. Course of disease is progressive, most of the patients die before 20. The diagnosis is often difficult. In our opinion in each case presenting psychomotor regression of unknown origin metabolic disease should be excluded (e.g. urine analysis for mucopolysaccharides should be indicated). A 6 year old boy has been under psychiatric and psychological control since he was 3 due to psychomotor retardation, hyperactivity, autistic features, and behavioural disorder. In paediatric examination thickened facial features, coarse hair, knock-knees, short neck were noted. Genetic consultation set up the diagnosis of mucopolysaccharidosis type IIIA (Sanfilippo A disease).

[Juvenile form of Huntington's disease--diagnostic problems]. / Dziecieca i mlodziencza postac choroby Huntingtona--problemy diagnostyczne.

Variability of clinical manifestation is an important feature of Huntington's disease (HD). It is due to the high instability of CAG sequences within a coding region of IT15 gene. We present five pedigrees in which apart from the adult form of HD the juvenile form of the disease affected some of the patients--as a result of genetic anticipation. Molecular analysis confirmed the well known fact that anticipation, which manifests itself by earlier onset of the disease in the subsequent generations, is strongly correlated with the degree of amplification of (CAG)n repeats in IT15 gene. An interesting feature of the presented data is the fact, that expansion of CAG repeats occurred not only at the paternal but also at the maternal transmission of the mutation. Some children in the presented HD pedigrees presented other neurological disturbances which could be suspected of HD; a molecular analysis revealing normal number of CAG repeats, enabled us to avoid misdiagnosis. The presented data provide evidence that clinical diagnosis of HD, particularly in cases with not very characteristic clinical picture--is not possible without DNA analysis--even in the families undoubtfully affected with the disease.

[Adrenomyeloneuropathy: a form of X-linked adrenoleukodystrophy. Report of a family]. / Adrenomieloneuropatia--jedna z postaci adrenoleukodystrofii sprzezonej z chromosomem X--badania rodziny.

A family with adrenoleucodystrophy linked to chromosome X (X-ALD) is reported. Three patients, one man (proband) and two female monozygotic twins, had adrenomyeloneuropathy (AMN) which is a form of the disease. The proband had characteristic changes in MRI with demyelination of the white matter in the cerebral hemispheres. Both women (one of them was proband's mother) has somewhat less severe AMN form, but in her twin sister the syndrome was much more intense. The clinical diagnosis of the disease was confirmed by biochemical investigations--determination of the level of very long chain fatty acids, ALDP protein and the activity of peroxysomal beta-oxidation.

[Mitochondrial diseases. Part I -- general review]. / Choroby mitochondrialne. czesc I -- ogólna.

Inborn mitochondrial diseases (MD) may result from molecular defects involving the mitochondrial or the nuclear genome, so they may be transmitted maternally or as Mendelian traits; some cases occur sporadically. Numerous secondary causes of mitochondrial disorders are also known. Impairment of mitochondrial oxidation leads to the defective energy production, and further, to cellular damage. MD should be suspected when progressive signs occur, especially involving nervous system and muscles; other organs as heart, liver and kidney may also be affected.

[Mitochondrial diseases. Part II -- diagnosis and detailed review]. / Choroby mitochondrialne. Czesc II -- Diagnostyka oraz czesc szczególowa.

The diagnosis of mitochondrial disease (MD) requires biochemical investigations of body fluids, particularly with respect to lactate and pyruvate elevation. Cardiological and ophtalmological examinations may also be helpful, as well as cerebral imaging. Tissue sampling, especially muscle biopsy and DNA analysis are important. Neuropathological findings consist of nonspecific spongiform lesions of gray matter, neuronal loss and sometimes demyelination with different topographic patterns. Some, more frequently occurring mitochondrial diseases and therapeutic attempts are reviewed.

Multinucleated giant cells in areas of the brain stem necrosis after cardiac arrest in two infants.

A rare type of cellular reaction in the brain stem of two infants with cardiac arrest encephalopathy is presented. After cardiac arrest both newborns were resuscitated and put on artificial ventilation. Their survival time amounted to 16 and 18 days, respectively, in a deep coma with areflexia. At the postmortem examination a widespread hemispheric necrosis of the gray and white matter was observed as well as symmetrical necrosis of the tegmental part of the brain stem extending from the midbrain up to medulla. Striking proliferation of blood vessels and large number of multinucleated giant cells originating from monocyte/macrophage lineage was found in the areas of the brain stem necrosis. No evidence of inflammatory process was found. It seems that giant cells appeared as local reaction on disintegration of maturing structures.

Immunological changes in the MPTP-induced Parkinson's disease mouse model.

The role of the central dopaminergic system in modulating immune response is not completely established. We examined the influence of central dopamine depletion on selected parameters of immune functions in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated and untreated mice. IgM antibody production of splenocytes to sheep red blood cells was reduced in MPTP-treated mice (P < 0.001). Proliferation of splenocytes in response to a wide range of mitogen concentrations (Concanavalin A, phytohaemagglutinin, lipopolysaccharide) was also significantly diminished in MPTP-treated mice. Production of migration inhibition factor (MIF) was diminished only in low mitogen concentration. Our results obtained in the experimental model of Parkinson's disease provide evidence that the damage of the central dopaminergic pathways induces alterations of some immune functions in mice.