Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy.

We report on a de novo interstitial deletion of chromosome 21q in a patient presenting with characteristic facial features, intellectual disability, and epilepsy. The deletion extent was about 4.9 Mb from position 37713441 bp (21q22.13) to position 42665162 bp (21q22.3) (NCBI36/hg18 map). Patients with partial monosomy 21 are quite rare; this anomaly has been associated with a wide spectrum of clinical signs, ranging from very mild to quite severe phenotypes. This variability results from variability in the deleted regions, thus accurate molecular definition of the chromosomal breakpoints is necessary to make better genotype-phenotype correlations. We compared our patient's phenotype with the few other patients reported in the literature and found to have similar deletion when analyzed by array CGH. The minimal overlapping region contains only two genes, DYRK1A and KCNJ6, which may play a major role in these patients' phenotype.

Pitt-Hopkins syndrome: report of a case with a TCF4 gene mutation.

AIMS: We will discuss the clinical and genetic diagnosis of a child with severe psychomotor delay, who at 3 years of age presented with paroxysms of hyperpnea-apnea and seizures unrelated to breathing anomalies. METHODS: The child underwent genetic (karyotype, FISH telomeres) and neuroradiological (cranial CT and MRI) tests, which proved to be normal. He came under our clinical observation at 3 years and 5 months of age. Due to severe psychomotor delay and facial dysmorphisms we completed the genetic investigations based on his clinical feature and analysis of the available literature. RESULTS: The presence of severe mental retardation associated with anomalous breathing pattern may suggest the Joubert and Rett syndrome, however these were excluded on the basis of clinical and genetic examination. Angelman syndrome, suspected for facial dysmorphisms and absent language, was also excluded because of the presence of a normal pattern of methylation at SNRPN locus. Another possible diagnosis was the Pitt-Hopkins Syndrome (PHS), characterized by severe mental retardation, breathing anomalies (paroxisms of hyperpnea-apnea), dysmorphisms and sometimes epilepsy. Haploinsufficiency of TCF4 gene located at 18q21.2 region has been recently identified as causative of this syndrome. In our patient the research of TCF4 mutation by the Institute of Human Genetics, University Hospital Erlangen (Germany), showed a de novo mutation. CONCLUSIONS: The diagnosis of Pitt-Hopkins syndrome, an underdiagnosed cause of mental retardation, was based on clinical and genetic findings. Searching for TCF4 mutations is highly recommended when others overlapping syndromes was excluded. At our knowledge our patient is the first italian case of PHS diagnosed at molecular level.

Molecular cytogenetic characterization of a translocation t(13;22)(q22.3;q11.23) in a patient with idiopathic partial epilepsy.

PURPOSE: We report on a balanced de novo translocation t(13;22)(q22.3;q11.23) in a patient with a form of focal idiopathic epilepsy. Since candidate genes for FPEVF (familial partial epilepsy with variable foci) have been mapped by linkage studies in the same cytogenetic band of chromosome 22 involved in the translocation, this case can be helpful to identify genes involved in this form of epilepsy. METHODS: Molecular cytogenetics analyses (FISH and array-CGH) were performed. RESULTS AND CONCLUSIONS: Neither DNA duplications nor deletions were detected by array-CGH, thus it can be inferred that the translocation is balanced. The breakpoint on chromosome 22 was precisely mapped by FISH on the RP11-432I9 clone, which is located in the interval defined by the linkage studies for FPEVF. The role of the known or hypothetical genes next to the 22q breakpoint is discussed.

Acute myelitis in a child: current hypotheses.

This report presents the case of a child with atopic dermatitis, who developed progressive muscular weakness and hypotonia of the four limbs. The cervical spinal cord magnetic resonance imaging revealed a C(4) lesion (T(2)-weighted images); the cerebrospinal fluid findings were normal. Treatment with intravenous immunoglobulins and methylprednisolone obtained rapid clinical improvement, and approximately 1 month later the small C(4) lesion disappeared. Various diagnostic hypotheses are discussed: acute myelitis by infective agents, acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis, multiple sclerosis, and isolated postinfective myelitis. Another hypothesis relates to atopic myelitis, a form recently described in the Japanese literature, associated with atopic dermatitis, hyperIgEemia, and high levels of specific immunoglobulin E to Dermatophagoides farinae and Dermatophagoides pteronyssinus. This diagnosis is difficult to confirm without biopsy evidence of eosinophilic inflammation.

Bartonella henselae infection associated with Guillain-Barre syndrome.

This is the first report of Guillain-Barré syndrome (GBS) related to Bartonella henselae infection. A 10-year-old girl had difficulty walking and marked myalgia. The search for all causes known to trigger GBS was negative. She was treated with intravenous immunoglobulins and recovered. Because she lived in a rural area and had a history of kitten contact, a specific serology for B. henselae infection was performed and confirmed an ongoing infection. She did not show any clinical typical feature of cat-scratch disease. B. henselae infection should be considered in the wide etiologic spectrum of GBS.

Migraine-like attacks in child with Sturge-Weber syndrome without facial nevus.

The Sturge-Weber syndrome was recently subdivided into type I (facial and leptomeningeal angioma, possible glaucoma), type II (facial angioma, without evident endocranial involvement), and type III (exclusive leptomeningeal angioma). Thus far in the literature only 24 cases of Sturge-Weber syndrome type III have been reported. This study presents a case of a 2-year 9-month-old child with normal psychomotor development and skin free (no angiomas), who presented repeated episodes of severe headache, vertiginous symptoms, vomiting, and drowsiness, separated by complete recovery. The cranial computed tomography and magnetic resonance imaging with gadolinium revealed left occipital leptomeningeal angiomatosis with calcifications, suggesting a diagnosis of Sturge-Weber syndrome type III. Considering the normal psychomotor development, the improved electroencephalographic reports between the episodes, and the absence of hypoperfusion areas on single-photon emission computed tomography at 30 months of follow-up, the symptomatology appears an expression of migraine-like symptoms resulting from vasomotor disturbances within and around the angioma, more than an expression of partial seizures arising through an epileptic focus in the ischemic region around the vascular malformation.

[Diagnosis of coeliac disease in patients with isolated neuropsychological symptoms. Cases reports]. / Diagnosi di malattia celiaca in pazienti con manifestazioni neurologiche e psichiche isolate: case report.

INTRODUCTION: After first report of Cooke e Smith, numerous are the reports of Coeliac Disease (CD) and neuropsychological symptoms association. The neuropsychological symptoms may precede or follow the diagnosis of CD, representing sometimes the only clinic manifestations (atypical forms). It's seem that frequency of unknown CD in patients with neuropsychological symptoms is about 16% and in a recent study about 7% of new cases of CD was diagnosed in order of neuropsychological disorders. To explain this clinical association various are the hypothesis proposed. CASE REPORTS: We report n degrees 4 cases (middle age 11 years and 2 months) come to our clinic for neuropsychological symptoms; all had diagnosis of CD (by serologic screening and intestinal biopsy); nobody had nutritional deficit, sideropenic anaemia or thyroid deficits. In all patients the introduction of dietetic therapy resolved the symptoms. CONCLUSION: These cases represent atypical forms of CD manifested in childhood only by neuropsychological disorders. To make an early diagnosis and to improve the disease prognosis, the literature and our clinic experience shown that is useful screen the CD in all patients with neuropsychological disorders such as epileptics foci in the parietal-occipital region and/or occipital calcification, headache (mostly if there isn't familiarity), spinocerebellar ataxia, neuromuscular disease of unknown aetiology, Down syndrome, behavioural disorders and some psychiatric troubles.

Periventricular nodular heterotopia: report of a pediatric series.

Periventricular nodular heterotopia is a malformation that occurs in both males and females and is associated with a variety of clinical and neuroradiologic signs. A gene called filamin-1 (FLN-1) has recently been identified. We review the clinical and imaging findings from a series of pediatric patients with periventricular nodular heterotopia. Five patients (three males and two females; age range = 4-18 years) were investigated. In our series, periventricular nodular heterotopia can be the common denominator in different conditions. Periventricular nodular heterotopia can occur alone or be associated with cortical malformations. Epilepsy was present in three of the five patients and was resistant to drugs in one female. Mental retardation was present in three of the five patients. Two male patients had normal intelligence, with no cortical anomalies; patient 3 had unilateral periventricular nodular heterotopia. The associated malformations were more severe in the female patients and slight only in patient 1. The two females showed anomalies rarely reported in association with bilateral periventricular nodular heterotopia. We believe that other genes can be involved in children with atypical neuroradiologic periventricular nodular heterotopia. No mutations were detected in 6 of the 48 exons of the FLN-1 gene, although this does not allow any definitive conclusions to be reached. We conclude that our series of patients with periventricular nodular heterotopia clearly highlights the complexity of the clinical, neurologic, and neuroradiologic characteristics associated with this malformation.