Marko Radoš

S-adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 μM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5–15.9 μM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was ≈3% of control in liver and was 5–10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patients cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.

S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy

SummaryS-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.

Smaller right hippocampus in war veterans with posttraumatic stress disorder

Chronic stress can putatively cause damage in the human hippocampus, but evidence of damage has not been consistently shown in studies on hippocampal morphology in posttraumatic stress disorder (PTSD). We compared hippocampal volumes in PTSD patients and normal subjects. Using a 3D T1-weighted GRE magnetic resonance imaging sequence, we measured hippocampal volumes in 15 war veterans with combat-related chronic PTSD and 15 case-matched normal controls. Although war veterans, our PTSD subjects were not professional soldiers and were mobilized shortly before they were exposed to a very specific combat-related trauma over a 3-day period. In our study, the period between traumatic exposure and imaging was considerably shorter, on average, 9 years, compared with at least two decades in previous studies on subjects with combat-related PTSD. Moreover, our subjects were free of any comorbidity, treatment or medication. The right hippocampus was significantly smaller in PTSD subjects than in healthy controls. The left hippocampus was also smaller in PTSD subjects than in controls, but the difference was not significant. In all PTSD subjects, the right hippocampus was smaller than the left (on average, 7.88%). Our results show smaller volume of the right hippocampus in PTSD patients than in normal subjects.

The differences of water diffusion between brain tissue infiltrated by tumor and peritumoral vasogenic edema

The differences between peritumoral brain tissue infiltrated by tumor and vasogenic edema were prospectively evaluated by comparing the apparent diffusion coefficient (ADC) of peritumoral areas of infiltrative tumors (anaplastic astrocytomas and glioblastomas) to that of peritumoral areas of noninfiltrative tumors (metastatic carcinomas) on 54 patients. Peritumoral ADCs indicated the possibility of differentiation between tumor infiltration and vasogenic edema, as well as between primary gliomas and metastases.

Characteristics of typical and atypical meningiomas on ADC maps with respect to schwannomas

The differences in apparent diffusion coefficient (ADC) between typical and atypical meningiomas and schwannomas were investigated, with 41 patients included in the study. There were no significant differences in ADC values or ADC ratios between typical and atypical meningiomas. The discrimination between schwannomas and the typical and atypical meningiomas on ADC maps was reliable, with significant differences in ADC values and ratios and with the narrow range of ADC values in meningiomas.

Enlargement of the spinal cord : Inflammation or neoplasm?

Intramedullary spinal tumours are uncommon lesions that can cause significant difficulties in the differential diagnosis between inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis, and vascular malformations or neoplasms. We report five cases in which the history and the clinical symptoms suggested an inflammatory process of the spinal cord but the MRI characteristics were those of neoplastic lesions. Both non-neoplastic and neoplastic intramedullary lesion may have very similar symptoms, and even CSF abnormalities, but in every one of our cases, a more detailed history and longer observation of the clinical course would have led to the correct diagnosis; in such problem cases, empirical treatment and a follow-up MRI after a months observation would be a more prudent approach providing that the patient is not rapidly deteriorating.

Isolated hypoglossal nerve palsy: a diagnostic challenge.

Hypoglossal nerve palsy (HNP) is not an uncommon finding in neurological diseases . However, when isolated, HNP can represent a diagnostic challenge in everyday clinical work and is limited to isolated case reports and few small case series . In this article, we report 4 patients with clinical presentation of isolated HNP due to different etiologies.

Antiphospholipid syndrome and central nervous system

Classification criteria, etiology, pathogenesis, major central nervous system (CNS) manifestations of the antiphospholipid syndrome (APS), as well as diagnostic and therapeutic approach are discussed in the article, supported by several MRI findings to illustrate differential complexity of selected topics. Close interplay of inflammation, autoimmunity, coagulation cascade, vasculature bed, neuron physiology and demyelinization in APS is elaborated. Cerebrovascular disease, multiple sclerosis-like syndrome, seizures, cognitive disfunction, headache and migraine, chorea and catastrophic antiphospholipid syndrome (CAPS) are discussed as the most prominent CNS manifestations of the APS.

Brain MRI abnormalities in ataxia-telangiectasia.

Background:Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, initially characterized by normal brain magnetic resonance imaging (MRI). Case report:In a 34-year-old woman patient with AT, MRI revealed extensive and diffuse white matter dismyelination, T1 and T2 hypointense lesions, T1 hypointense but T2 hyperintense lesions, and numerous dilated telangiectases upon gadolinium enhancement. Discussion:In our patient, brain MRI confirmed extensive extracerebellar lesions in AT. Conclusion:Our report broadens the spectrum of brain MRI abnormalities in AT and supports the hypothesis on cerebrovascular abnormalities occurring in later stages of AT.

Doppler visualization of ureteric jets in unilateral hydronephrosis in children and adolescents.

OBJECTIVE to evaluate Doppler visualization of ureteric jets in the assessment of unilateral kidney collecting system dilatation in children and adolescents. METHODS AND PATIENTS color Doppler ultrasonography was performed in 27 patients with hydronephrosis (11 female, 16 male, age range 3-21 years, mean age 10.5+/-4.4). Nine had acute obstruction due to ureteral calculus, seven had obstructive hydronephrosis due to uretero-pelvic junction (UPJ) stenosis, and 11 had non-obstructive hydronephrosis. Doppler was also performed in 32 healthy children (15 boys and 17 girls, age 2-17 years, mean age 7.8+/-3.9), who represented the control group. RESULTS in the control group jets were visible in 57 out of 64 ureteric units (89%). The mean frequency of jets in healthy children was 4.1 jets per min. In all children with hydronephrosis, jets were visible in 25 out of 27 normal ureteric units (92.6%), and their mean frequency was 4.5 jets per min. In children with acute unilateral colic, ureteric jets were completely absent in eight of nine patients (89%). In children with obstructive hydronephrosis, due to UPJ stenosis, jets were absent in five out of seven patients (71.4%), and in children with non-obstructive hydronephrosis jets were absent in three out of eleven patients (27.3%). When jets are visible, their frequencies are much lower on the obstructed side as compared with normal side, while in cases of nonobstructive dilatation frequency of jets is similar on both sides. CONCLUSION absence of jets in patients with acute obstruction due to ureteral calculus, strongly correlates with high-grade obstruction. In children with UPJ stenosis, presence of ureteric jet does not exclude significant obstruction, but the frequency of jets on the obstructed side is much lower as compared with the unaffected side. When there is absence of jet from the dilated side or significant asymmetry in jet frequency, hydronephrosis is likely to be obstructive.