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.*Correspondence: Department of Pediatrics, University Hospital Center, Kišpatićeva 12, Rebro, 10000 Zagreb, Croatia. E-mail: ibaric@kbc-zagreb.hr. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptS-Adenosylhomocysteine (AdoHcy) hydrolase (adenosylhomocysteinase, EC 3.3.1.1) is the enzyme that catalyses hydrolysis of AdoHcy to adenosine and homocysteine (De La Haba and Cantoni 1959). Its deficiency (McKusick 180960) had been proven in a human only once, in a Croatian boy we reported recently (Barić et al 2004). The index patient presented with myopathy, characterized by hypotonia and delayed psychomotor development from birth, abnormally slow brain myelination (noted in MRI studies of the brain at 12.7 months) and mild hepatitis-like findings. The main biochemical abnormalities were marked increases of creatine kinase and aminotransferases, prolonged prothrombin time, low albumin, and specific amino acid aberrations indicative of the aetiology: hypermethioninaemia with almost normal total plasma homocysteine and very elevated plasma AdoHcy (up to 150 × normal) and SAdenosylmethionine (AdoMet) (up to 30 times normal). Activity of AdoHcy hydrolase was severely diminished: about 3% of control in liver and 9−15% of the mean controls in fibroblasts and red blood cells. The specific metabolic defect had been identified and the patient started on therapy by age 12.8 months. Here we report a second patient (patient 2), a brother of the proband. Patient 2 has been monitored since birth and was started on therapy at age 3.4 months, by which time the diagnosis of AdoHcy hydrolase deficiency had been clearly established. We report, also, outcomes during therapy in both patients. METHODS Metabolite assaysAmino acids were measured by i...

Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. 25Mg2+ uptake assays demonstrated loss‐of‐function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44–0.72 mmol/L), which could not be fully corrected by Mg2+ supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR.

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We report the case of a 4-year-old boy who first presented with acute pyelonephritis at the age of 6 months. Diagnostic workup revealed high-grade bilateral vesicourethral reflux (VUR). At the age of 18 months, a bulking agent was used to treat bilateral VUR. Since the VUR persisted, an open bilateral Lich-Gregoir procedure was done at the age of 3 years. Immediately after surgery, he developed acute urinary retention with hydronephrosis that resolved with the placement of dwelling urinary catheter. After removal of the catheter urinary retention relapsed so placement of suprapubic urinary catheter was indicated since he did not have sensory loss. He was started with tamsulosin (α − 1-blocker) and prophylactic antibiotics. Urodynamics were performed and suggested bladder outlet obstruction. On the basis of previous urethroscopy and the absence of neurological sequelae, the differential diagnosis of Hinman syndrome was made. After removal of the suprapubic catheter, clean intermittent catheterization was started and α-blocker continued. However, magnetic resonance imaging of the brain and the spinal cord revealed syringohydromyelia extending from thoracic spine (Th5) to conus medullaris with 6 to 7 mm in diameter. Electromyoneurogram was normal. After a follow-up of 3 years, the hydronephrosis has resolved. The patient is on clean intermittent catherization and has no urinary tract infections.

anomalies, and a typical number of other phenotypes, including occurrence of cardiac fibroma. The syndrome is caused by microdeletion of the long arm of chromosome 9, in the region q22.3-q31 which includes the PTCH tumor suppressor gene. The diagnosis is made clinically, through large and small criteria that include the already mentioned clinical characteristics.Case Report We will present the case of a 5yearold girl diagnosed with Gorlin -Goltz syndrome with the presence of fibroma in the left ventricular wall. The patient has an uneven psychomotor development and shows atypicalities in the field of socio-emotional functioning. Phenotypically, we find increased neurocranium, rough facial features, divergent strabismus, and a wider nasal root. The girl was initially hospitalized for the clinical presentation of heart failure: she was clinically tachydyspnoic, with audible crepitations in the lungs, enlarged liver, and pretibial edema. Echocardiographically, it was diagnosed with dilated cardiomyopathy, with an ejection fraction of 25%, while the formation of an unclear etiology was seen in the left ventricle. The patient was treated with anticongestive therapy with low molecular weight heparin and further treatment was performed. MRI of the heart showed a formation that according to radiological criteria corresponds to a large fibroma. Due to the opinion that dilated cardiomyopathy and fibroma with phenotypic characteristics could be parts of systemic disease, molecular karyotyping was performed which found microdeletion of the long arm of chromosome 9 in the q22.3 region, which includes the PTCH gene that regulates cell growth and functions as a tumor suppressor gene. Haploinsufficiency of this gene has been described as Gorlin -Goltz syndrome, which is characterized by phenotypic traits such as those found in our patient. Among patients with Gorlin-Goltz syndrome, 10% develop cardiac fibroma with the most common localization in the left ventricular cavity. Symptoms of cardiac fibroma depend on the size of the tumor, the involvement of the conduction system, and the possible existence of intracavitary obstruction. The patient we present has an extensive tumor located intramurally in the anterolateral wall of the left ventricle, measuring 5.8x4.8 cm. Measured values of cardiac pressures obtained by invasive cardiac treatment indicate impaired systolic and diastolic heart function and increased pulmonary pressure, as a result of dilated cardiomyopathy with clinical signs of heart failure. Discussion The presence of dilated cardiomyopathy with markedly impaired systolic function may be secondary to the tumor or as primary disease, that is why genetic processing of cardiomyopathy is ongoing. Cardiac fibroma can be treated by surgical resection, but in a situation of severely impaired systolic function, transplantation treatment is more likely, with the risk of immuosuppression in a patient with a tumor suppressor gene disorder.