Widening the phenotypic spectrum - Non epileptic presentation of folate transporter deficiency.

INTRODUCTION: Folate is essential for production of DNA, neurotransmitters and myelin and regulation of genetic activity. A specific transporter protein is required to transport folate from blood to CSF. Various inherited brain-specific folate transport defects have been recognized due to mutation in Folate Receptor alpha (FOLR1). FOLR1 mutation is one of the vitamin responsive encephalopathies and is inherited as an autosomal recessive condition. It has a wide spectrum of phenotype, commonly presenting as epileptic encephalopathy. Less frequently the condition may manifest with subtle hypotonia, movement disorder as tremors, ataxia or intellectual disability and autistic spectrum disorder. We present a case of folate transporter deficiency with non-epileptic manifestations, presenting with tremors, speech delay and stable white matter changes in MRI brain. OBJECTIVE: We present a case of Folate transporter defect with Non-epileptic presentation. CONCLUSION: Folate transporter deficiency has a wide range of presenting symptoms. Presentation with slowly progressive atypical symptoms, stable white matter changes in brain MRI that does not fit a specific diagnosis, should raise a high suspicion of FOLR1 mutation, even in absence of seizures. Since folate transporter deficiency is a treatable neurodegenerative disorder, early diagnosis and supplementation with folinic acid is vital.

Clinical relevance of trace element measurement in patients on initiation of parenteral nutrition.

Background and Aims Serum zinc, copper and selenium are measured in patients prior to commencing on parenteral nutrition; however, their interpretation can be difficult due to acute phase reactions. We assessed (i) the relationship of raised C-reactive protein with trace elements and albumin (ii) benefits of measuring trace elements when C-reactive protein is raised in patients requiring short-term parenteral nutrition. Methods Samples were collected for zinc, copper, selenium and albumin at baseline and then every two weeks and correlated with C-reactive protein results in patients on parenteral nutrition. Results were categorized into four groups based on the C-reactive protein concentrations: (i) <20 mg/L, (ii) 20-39 mg/L, (iii) 40-79 mg/L and (iv) ≥80 mg/L. Results In 166 patients, zinc, selenium and albumin correlated (Spearman's) negatively with C-reactive protein; r = -0.26, P < 0.001 (95% CI -0.40 to -0.11), r = -0.44, P < 0.001 (-0.56 to -0.29) and r = -0.22 P = 0.005 (-0.36 to -0.07), respectively. Copper did not correlate with C-reactive protein (r = 0.09, P = 0.25 [-0.07 to 0.25]). Comparison of trace elements between the four groups showed no difference in zinc and copper (both P > 0.05), whereas selenium and albumin were lower in the group with C-reactive protein > 40 mg/L ( P < 0.05). Conclusion In patients on short-term parenteral nutrition, measurement of C-reactive protein is essential when interpreting zinc and selenium but not copper results. Routine measurement of trace elements prior to commencing parenteral nutrition has to be considered on an individual basis in patients with inflammation.

Environmental enteropathy.

PURPOSE OF REVIEW: Environmental enteropathy has long been recognized as an important intermediary condition leading to chronic malnutrition in children in developing countries. Interest has lately renewed in this topic because of increased focus on improving the quality of lives as opposed to just saving them. Here, we provide an overview of recent scientific literature and our perspective about this disorder. RECENT FINDINGS: Current understanding of the disorder of environmental enteropathy is based on studies conducted decades ago. Results of some new studies on histopathologic characterization of environmental enteropathy are currently awaited. Given the challenges of diagnosing environmental enteropathy using the gold standard test of intestinal biopsy, different biomarkers have been tested as proxies of environmental enteropathy and eventually, chronic malnutrition. Available data fail to point toward a single ideal biomarker, though considerable work is still ongoing. A few interventional studies have also been conducted with improvement in environmental enteropathy as outcome. SUMMARY: The basic histopathology of environmental enteropathy has been defined previously, and more advanced analysis to study the pathophysiology of this disorder is currently being carried out. Many biomarkers, which represent the different mechanisms involved in environmental enteropathy, have been tested as proxies of environmental enteropathy. Although no single biomarker fits the description of an ideal biomarker yet, a few of the more promising biomarkers are being validated in different studies. Finally, the few interventions which have been tried to treat environmental enteropathy, thus far, are summarized.

Failure to thrive and life-threatening complications due to inherited selective cobalamin malabsorption effectively managed in a juvenile Australian shepherd dog.

A juvenile Australian shepherd dog exhibited failure to grow, inappetence, weakness, nonregenerative anemia, neutropenia, and cobalamin deficiency. DNA testing confirmed homozygosity of an amnionless mutation (AMN c.3G > A). Clinical signs resolved with supportive care and parenteral cobalamin supplementation. Inherited selective intestinal cobalamin malabsorption requiring lifelong parenteral supplementation should be considered in Australian shepherds, giant schnauzers, border collies, and beagles that fail to thrive.

Gestion efficace d'un retard de croissance et de complications potentiellement mortelles attribuables à une malabsorption de cobalamine sélective héréditaire chez un jeune chien Berger australien. Un jeune chien Berger australien a manifesté une absence de croissance, de l'inappétence, de la faiblesse, une anémie non régénérative, de la neutropénie et une déficience de cobalamine. Des tests d'ADN ont confirmé l'homozygotisme d'une mutation des récepteurs amnionless (AMN c.3G > A). Les signes cliniques se sont résorbés avec des soins de soutien et des suppléments de cobalamine parentéraux. Une malabsorption intestinale sélective héréditaire de cobalamine exigeant des suppléments parentéraux à vie devrait être considérée chez les Bergers australiens, les Schnauzers géants, les Border-Collies et les Beagles qui manifestent des problèmes de croissance.(Traduit par Isabelle Vallières).

The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1.

BACKGROUND: Hereditary folate malabsorption is a rare, autosomal recessive disorder of proton-coupled folate transporter deficiency resulting in folate deficiency. Left untreated, the condition can cause severe brain damage and megaloblastic anemia, leading to progressive psychomotor retardation, seizures and other neurological problems. Early diagnosis and treatment are crucial. No case has been documented yet in Mainland China until now. METHODS: A Chinese girl affected by hereditary folate malabsorption was studied. The girl presented with recurrent megaloblastic anemia from the age of 7 months. Paroxysmal limbs trembling and seizures were presented from the age of three years. Intracranial calcification was noted by CT. At her age of 5 years, mental regression, lower-extremity weakness and sleeping problems were observed. Her plasma folate decreased to 4.49 nmol/L (normal control>6.8nmol/L). Plasma total homocysteine elevated to 28.11 µmol/L (normal control<15 µmol/L). Folate and 5-methylterahydrofolate in cerebrospinal fluid were significantly decreased to undetectable level. RESULTS: On SLC46A1 gene, a novel mutation, c.1A>T (M1L), and a reported mutation c.194-195 insG (p.Cys66LeufsX99) were identified, supported the diagnosis of hereditary folate malabsorption. Each parent carries one of two mutations. Folinic calcium supplement resulted in rapid clinical improvement. She is currently 6 years old with normal development and routine blood features. CONCLUSION: Hereditary folate malabsorption is one of the few easily-treatable inherited metabolic diseases. Measurements of folate and 5-methyltetrahydrofolate in cerebrospinal fluid are keys for the diagnosis of the patients.

Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence.

BACKGROUND: Anderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the SAR1B gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal SAR1B gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7). METHODS AND RESULTS: The patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the SAR1B gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes. CONCLUSIONS: This patient with AD/CMRD has a normal SAR1B gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine.

Brown bowel syndrome secondary to jejunoileal bypass: the first case report.

A 58-year-old woman with a surgical history of jejunoileal bypass in 1980 for weight reduction sought medical attention with multiple complaints. The patient had not been taking any nutritional supplements since her bypass surgery, 26 years previously. She was found to have osteomalacia, chronic diarrhea, secondary hyperparathyroidism, and hyperoxaluria with a frequent history of nephrolithiasis. Because of her severe osteodystrophy and metabolic complications, reversal of her jejunoileal bypass was recommended. Reversal of the jejunoileal bypass with a sleeve gastrectomy was performed. Laparotomy revealed brown discoloration of the entire alimentary limb with atrophy of the bypassed intestinal limb. Histologic examination of the resected small bowel demonstrated brown pigment deposits within smooth muscle cells of the bowel wall. The pigment stained positive with Fontana-Masson most likely representing lipofuscin. We report a case of brown bowel syndrome complicating jejunoileal bypass, the first case reported in the literature to the best of our knowledge.

Primary intestinal lymphangiectasia (Waldmann's disease).

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool alpha1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur.

Fulminant heart failure due to selenium deficiency cardiomyopathy (Keshan disease).

Selenium deficiency is a rare cause of cardiomyopathy that may be encountered by the forensic pathologist. Selenium deficiency is associated with a cardiomyopathy, myopathy and osteoarthropathy. In Asia and Africa, dietary selenium deficiency is associated with a cardiomyopathy known as Keshan disease and an osteoarthropathy called Kashin-Beck disease. Chronic selenium deficiency may also occur in individuals with malabsorption and long term selenium-deficient parenteral nutrition. Selenium deficiency causes myopathy as a result of the depletion of selenium-associated enzymes which protect cell membranes from damage by free radicals. We present a case of fulminant heart failure in a middle aged woman with a complex medical and surgical history including documented malabsorption and selenium deficiency. Pathological examination of the heart showed features consistent with Keshan disease.

Suplementación de DL-Ó-tocoferol acetato oral en niños con colestasis crónica y déficit de vitamina E / Supplement of Oral DL-Ó-Tocopherol Acetate in children with chronic cholestasis and vitamin E deficit

Objetivo. Determinar la dosis oral suplementaria de dl-Ó-tocoferol acetato para mantener niveles séricos de Ó-tocoferol normales en niños con colestasis crónicas y déficit de vitamina E. Antecedentes. La malabsorción y deficiencia de vitamina E en niños con colestasis crónica se presenta en un 60-70 por ciento, causando un síndrome de degeneración neurológica progresiva entre 18 y 24 meses si no se corrige. La pronta suplementación con vitamina E determina la prevención e irreversibilidad de dicho déficit. Método. Realizamos un estudio prospectivo, longitudinal y comparativo de 60 niños divididos en tres grupos, con déficit de vitamina E y colestasis crónica. Luego de una evaluación inicial y por 15 días, cada grupo recibió suplementación oral con 100 UI, 200 UI y 400 UI diarias de dl-Ó-tocoferol acetato, respectivamente. Fueron monitorizados los niveles séricos de Ó-tocoferol, la función neurológica y los parámetros bioquímicos durante la suplementación. Resultados. Ninguna de las dosis suplementarias orales de dl-Ó-tocoferol acetato administradas por 15 días normalizaron los niveles séricos de Ó-tocoferol (p>0.06). La función neurológica, que no encontraba alterada al inicio del estudio en ninguno de los pacientes, permaneció estable luego de los 15 días, a dosis de 100 UI, 200 UI y 400 UI, a pesar de ser seguro, no mantuvo los niveles séricos normales de Ó-tocoferol en niños con colestasis crónica y déficit de vitamina E

Small bowel biopsy through an enteroclysis catheter to augment findings at enteroclysis and hypotonic duodenography.

Proximal jejunal mucosal biopsy was performed by a radiologist through the nasojejunal catheter at the time of enteroclysis. Seventeen patients (10 men and seven women, aged 23-73 years [mean, 46 years]) were studied with enteroclysis because of clinical signs of malabsorption with suspected small bowel disease. In seven (41%) patients, results at biopsy were positive, and results in another seven (41%) were positive at enteroclysis. In 10 (59%) patients, results were positive at one or both tests. Performance of both small bowel biopsy and enteroclysis at the same session is feasible and offers additional clinically pertinent information than can be obtained at enteroclysis alone.

Brown bowel syndrome: report of two cases.

Brown bowel syndrome is a rare intestinal disorder associated with the deposition of lipofuscin pigment in the smooth muscle cells. We report two such cases presenting with intestinal pseudo-obstruction, abdominal pain, and body weight loss. Both cases had malabsorption and fatty liver. Exploratory laparotomy revealed brownish discoloration of the small bowel wall and enlargement of mesenteric lymph nodes. Light microscopy, autofluorescence and ultrastructure studies confirmed the deposition of lipofuscin pigments in the intestinal muscle cells and reticuloendothelial cells of mesenteric lymph nodes. In addition, the calf muscle biopsy of case 1 displayed myopathy and fatty replacement. Skeletal muscle strength of both patients was partially restored after parenteral and oral vitamin E supplement and other conservative treatment, but gastrointestinal symptoms of both patients continued to deteriorate. Thus, brown bowel syndrome associated with prolonged and severe malnutrition and possibly vitamin E deficiency appears only partially responsive to vitamin E supplementation.

Rhabdomyolysis after intramuscular iron-dextran in malabsorption.

The case of a 59 year old white man who had chronic malabsorption and selective IgA deficiency with severe iron deficiency is reported. In addition, he was deficient in vitamin E and selenium, important antioxidants which protect against lipid peroxidation. He was intolerant of oral iron and when treated with iron-dextran developed symptoms suggestive of polymyositis with evidence of rhabdomyolysis. It is suggested that free iron within iron-dextran activated free radicals, initiating lipid peroxidation and leading to polymyositis, rhabdomyolysis, and myoglobulinuria.

Probable vitamin K--deficient bleeding in two cats with malabsorption syndrome secondary to lymphocytic-plasmacytic enteritis.

Two cats with intestinal malabsorption developed a hemorrhagic diathesis. Although unsubstantiated, the probable cause of bleeding was a chronic malabsorption of fat and the fat-soluble vitamin K. When treated with vitamin K1 per os, one cat's clotting times were only partially corrected. Since vitamin K1 is actively absorbed in the proximal small intestine, the incomplete response of this case to orally administered vitamin K1 was predictable. The infrequent occurrence of bleeding in animals with malabsorption is, in part, attributable to the ileal and colonic absorption of bacterially derived vitamin K2. For this reason, nonspecific use of antibiotics in these animals is contraindicated. Since long-chain, polyunsaturated fats impair vitamin K absorption, dietary fat given to animals with malabsorption should be restricted to medium- and short-chain, saturated fats. Vitamin K should be administered subcutaneously to these animals if prolonged clotting times or active bleeding is present, and routinely prior to surgery. Oral supplementation with vitamin K3, which is absorbed in the colon and less lipid soluble than vitamin K1, should be given to animals with malabsorption that are maintained as outpatients. Adequate dosage levels of vitamin K3, however, are yet to be established for the cat, and dose-dependent hemolytic anemia is a probable toxic manifestation.

Accumulation of ceroid in smooth muscle indicates severe malabsorption and vitamin E deficiency.

Four patients had accumulation of ceroid in smooth muscle (lipofuscinosis), which indicated severe or uncontrolled malabsorption, with confirmed vitamin E deficiency in three cases. The distribution of the pigment was systematic, and there seemed to be an association between malabsorption syndrome and vitamin E deficiency. Vitamin E supplementation seems to be indicated in such patients, and it is suggested that studies of smooth muscle function should be made in cases of heavy accumulation of ceroid.

Prurigo nodularis associated with malabsorption.

The case of a 72-year-old female with a syndrome of malabsorption associated with prurigo nodularis is reported. The patient had been suffering from these disorders for 16 years. The pathological alteration of her malabsorption syndrome was an idiopathic sprue. 5 months after treatment with gluten-free diet supplemented with vitamins and iron, the disappearance of the clinical and analytical alterations was complete.

Zinc therapy in acrodermatitis enteropathica.

An infant is described with acrodermatitis enteropathica, who initially presented with severe and intractable watery diarrhea. Diagnosis was established at the age of eleven weeks. Serum-zinc concentrations were extremely low and urinary zinc excretion was diminished. Eleven days after oral zinc supplement (100 mg elemental zinc per day), the skin lesions had healed. The high therapeutic doses of zinc required for healing are suggestive that zinc malabsorption is an important pathogenetical factor of this disease.