COVID-19 and Hartnup disease: an affair of intestinal amino acid malabsorption.

Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies currently exist, and different clinical phenotypes complicate the situation. In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. Understanding the mechanism of GI disturbances is warranted for exploring better clinical care for COVID-19 patients. With evidence collected from clinical studies on COVID-19 and basic research on a rare genetic disease (i.e., Hartnup disorder), we put forward a novel hypothesis to elaborate an effective nutritional therapy. We hypothesize that SARS-CoV-2 spike protein, binding to intestinal angiotensin-converting enzyme 2, negatively regulates the absorption of neutral amino acids, and this could explain not only the GI, but also systemic disturbances in COVID-19. Amino acid supplements could be recommended.Level of evidence No level of evidence: Hypothesis article.

Severe persistent unremitting dermatitis, chronic diarrhea and hypoalbuminemia in a child; Hartnup disease in setting of celiac disease.

BACKGROUND: Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. CASE PRESENTATION: We report a 3-year girl with chronic diarrhea, Hypoalbuminemia and exfoliative erythema. She was diagnosed with celiac disease, which did not improve on gluten free diet. Hartnup disease was suspected and was confirmed by neutral aminoaciduria. Niacin was started and followed by dramatic improvement. CONCLUSION: Presence of Celiac and Hartnup disease in single individual is very rare. Complete nutritional assessment of refractory celiac patient can reveal underlying nutritional deficiency.

Hartnup disease masked by kwashiorkor.

This report describes an 11-month old girl with Hartnup disease presenting with kwashiorkor and acrodermatitis enteropathica-like skin lesions but free of other clinical findings. This case with kwashiorkor had acrodermatitis enteropathica-like desquamative skin eruption. Since zinc level was in the normal range, investigation for a metabolic disorder was considered, and Hartnup disease was diagnosed.

Novel mutation in SLC6A19 causing late-onset seizures in Hartnup disorder.

Hartnup disorder is caused by an inborn error of neutral amino acid transport in the kidneys and intestines. It is characterized by pellagra-like rash, ataxia, and psychotic behavior. Elevated urinary neutral amino acids are the first indicator of the disorder. SLC6A19 was identified as the causative gene in autosomal-recessive Hartnup disorder, which encodes the amino acid transporter B(0)AT1, mediating neutral amino acid transport from the luminal compartment to the intracellular space. Here, we report on a Korean boy aged 8 years and 5 months with Hartnup disorder, as confirmed by SLC6A19 gene analysis. He manifested seizures, attention-deficit hyperactivity disorder, and mental retardation without pellagra or ataxia. Multiple neutral amino acids were increased in his urine, and genetic analysis of SLC6A19 revealed compound heterozygous mutations, c.908C>T (p.Ser303Leu) and c.1787_1788insG (p.Thr596fsX73), both of which are novel. A novel SLC6A19 gene mutation was associated with late-onset seizures in a Korean patient with Hartnup disorder.

Severe exfoliative erythema of malnutrition in a child with coexisting coeliac and Hartnup's disease.

Exfoliative erythema of malnutrition is a collective term for skin lesions caused by a combination of multiple deficiencies in vitamins, microelements, essential fatty acids and amino acids. We report a 3-year-old Iraqi girl with malnutrition due to coexisting coeliac and Hartnup's disease. On admission to hospital, she presented with kwashiorkor, anaemia, hepatitis and hypoalbuminia. She had severe skin changes with erythema, desquamation, erosions and diffuse hyperpigmentation involving the whole integument, particularly the perioral area, trunk and legs. She also had angular cheilitis, glossitis, conjunctivitis and diffuse alopecia. After treatment with a high-protein gluten-free diet and supplementation with vitamins and microelements there was a rapid improvement in the skin lesions. The severity of the skin lesions in this case can be explained by the coexistence of two metabolic diseases causing complex malnutrition.

Manifestaciones anatomoclínicas de las enfermedades cutáneas metabólicas y sistémicas misceláneas: Parte II / Anatomoclinical manifestations of metabolic and systemic diseases: Part II

Numerosas enfermedades sistémicas y metabólicas tienen manifestaciones cutáneas, muchas de estas manifestaciones pueden favorecer su diagnóstico. Dado el gran número de estas patologías, esta revisión no pretende ser un análisis exhaustivo de todas ellas, sino que presenta un análisis clínico-patológico de algunas enfermedades metabólicas y sistémicas seleccionadas.

Numerous systemic and metabolic diseases have coetaneous manifestations, many of these manifestations can favor diagnosis Due to the great number of these conditions, this review does not try to be a comprehensive analysis of all of them, but present a clinicopathological analysis of some selected metabolic and systemic diseases.

Acrodermatitis enteropathica-like eruptions in a child with Hartnup disease.

Acrodermatitis enteropathica-like eruptions, not related to zinc deficiency, have been rarely reported in some metabolic disorders. Reported patients usually had low levels of essential amino acids, particularly isoleucine. Here we report a girl who first presented with an acrodermatitis enteropathica-like eruption and eventually had the diagnosis of Hartnup disease with a normal isoleucine level. We discuss the probable cause of her skin lesions and the differential diagnosis with pellagra.

[Clinical studies of pediatric malabsorption syndromes].

Multiple cases with various types of pediatric malabsorption syndromes were evaluated. The clinical manifestations, laboratory findings, pathophysiology, and histopathological descriptions of each patient were analyzed in an effort to clear the pathogenesis of the malabsorption syndromes and the treatments were undertaken. The cases studied, included one patient with cystic fibrosis, two with lactose intolerance with lactosuria (Durand type), one with primary intestinal lymphangiectasia, two with familial hypobetalipoproteinemia, one with Hartnup disease, one with congenital chroride diarrhea, one with acrodermatitis enteropathica, one with intestinal nodular lymphoid hyperplasia (NLH), five with intractable diarrhea of early infancy and four with glycogenosis type Ia. Each case description and outcome is described below: 1. A 15-year-old Japanese boy with cystic fibrosis presented with severe symptoms, including pancreatic insufficiency, bronchiectasis, pneumothorax and hemoptysis. His prognosis was poor. Analysis of the CFTR genes of this patient revealed a homozygous large deletion from intron 16 to 17b. 2. In the sibling case of Durand type lactose intolerance, the subjects'disaccaridase activity of the small bowel, including lactase, were within normal limits. The results of per oral and per intraduodenal lactose tolerance tests confirmed lactosuria in both. These observations suggested, not only an abnormal gastric condition, but also duodenal and intestinal mucosal abnormal permeability of lactose. 3. In the case of primary intestinal lymphangiectasia, the subject had a lymphedematous right arm and hand, a grossly coarsened mucosal pattern of the upper gastrointestinal tract (identified via radiologic examination) and the presence of lymphangiectasia (confirmed via duodenal mucosal biopsy). The major laboratory findings were hypoalbuminemia, decreased immunoglobulin levels and lymphopenia resulting from loss of lymph fluid and protein into the gastro-intestinal tract. 4. In two cases of heterozygous familial hypobetalipoproteinemia, serum total cholesterol and betalipoprotein levels were very low. The subjects presented with symptoms and signs of acanthocytosis and fat malabsorption. Further, one subject had neurological abnormalities such as mental retardation and severe convulsions. Treatment with MCT formula diet corrected the lipid malabsorption. 5. A 5-year-old girl presented with pellagra-like rashes, mental retardation and cerebellar ataxia. An oral tryptophan (Trp) and dipeptide (Trp-Phe) loading test were conducted and the renal clearance of amino acids was also evaluated in this patient and in controls. Following the oral Trp loading test, plasma levels of Trp indicated a lower peak in the case, reaching a maximum at 60 minutes. On the other hand, the oral dipeptide (Trp-Phe) loading test in the Hartnup patient showed the peak Trp plasma level was the same as the control subjects. The renal clearance of neutral amino acids in this case increased to levels 5 to 35 times normal. 6. In the case of congenital chloride diarrhea, the subject had secondary lactose intolerance, dehydration, hyponatremia, hypokalemia, hypochloremia, hyperreninemia and metabolic alkalosis. The chloride content of her fecal fluid was very high. The concentrations were 89-103 mEq/l. In contrast, her urine was chloride-free. The subject's growth and development improved after treatment with lactose free formura and oral replacement of the fecal loses of water, NaCl and KCl. Unfortunately, the patient died of a small bowel intussusception. The kidney histopathological finding was juxtaglomerular hyperplasia by a necropsy. 7. In the case of acrodermatitis enteropathica, the subject had characteristic skin lesions, low serum zinc levels and ALPase activity. An oral ZnSO4 loading test and intestinal mucosal histology by a peroral biopsy were conducted. The serum zinc peak level was 2 hours after the oral ZnSO4 loading test. Infant formula alone could not maintain normal serum zinc ranges. Light microscopic studies of the intestinal villous architecture showed a normal pattern. However, ultrastructual examination of several epithelial cells revealed numerous intracellular vesicles. After zinc therapy, these changes were decreased. The lesions were postulated as the secondary result of zinc deficiency. 8. A 12-year-old girl presented with hypogammaglobulinemia, recurrent infections, chronic diarrhea and intestinal NLH. A barium meal and follow-through examination showed multiple nodules throughout the stomach and intestine. The nodules, all uniform in size, were 2 mm diameter. The barium enema did not show NLH in the colon. Mucosal biopsy of the stomach and jejunum revealed the typical histology of NLH in the lamina propria. Also, achlorhydria was present in this patient and her serum gastrin levels were very high; 315-775 pg/ml. 9. In 4 cases of intractable diarrhea in early infancy (by Avery G B), a jejunal biopsy showed shortening villi and nonspecific enterocolitis. Some patients were found with only low lactase or low lactase and sucrase levels. An electron microscope analysis of the small bowel in 2 cases showed alterations: increased pinocytosis in microvillus membranes and lysosomes by endocytosis of undigested macromolecular substances. I postulated that the stated evidence was causative of this clinical profile. 10. I frequently observed diarrhea as a clinical manifestation in glycogenosis type Ia and lipid malabsorption in one case. The light and electron photomicrographs showed intestinal absorption cells with the glycogen deposits in the inferior devision of nuclei.

Spontaneous scalp arteriovenous fistula in a child with hartnup disease.

PURPOSE: To report the endovascular treatment of a spontaneous scalp arteriovenous fistula (AVF) in a child with Hartnup disease. CASE REPORT: A 6-year-old girl with Hartnup disease presented with recurrent attacks of intense, migraine-like, right-sided headache; a tender, pulsatile small mass was observed in the scalp. Selective digital subtraction angiography revealed a high-flow scalp AVF fed by the frontal branch of the right superficial temporal artery draining via the scalp veins. Endovascular treatment was performed by direct puncture of the distal feeding artery and injection of 2 mL of a 50% mixture of N-butyl-cyanoacrylate and Lipiodol. Serial arteriograms performed 6 months and 2 years later documented complete resolution of the lesion. The patient has had no recurrence of clinical symptoms or local signs for recanalization. CONCLUSIONS: Scalp AVFs may progress in size, causing significantly disabling symptoms, particularly in children. We recommend endovascular treatment at the earliest possible stage.

Hartnup disease presenting in an adult.

A young woman presented with pellagra. Her symptoms were precipitated by prolonged lactation and increased activity. Dietary intake of niacin was within recommended guidelines. Chromatography of urinary amino acids was diagnostic of Hartnup disease, an inherited disorder usually presenting in childhood. Her symptoms resolved with oral nicotinamide.

Intermittent dystonia in Hartnup disease.

A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-indoleacetic acid concentration was less than or equal to 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two-fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; however, trihexyphenidyl (1-2 mg/kg/day) dramatically improved it. Hartnup disease should be considered in children with unexplained dystonia.

Biochemical screening for inherited metabolic disorders in the mentally retarded.

A biochemical screening programme for the detection of inherited metabolic disease was carried out on urine and blood samples from inmates of the Alexandra Institute for the mentally retarded, Cape Town. Of the 1087 patients screened, positive results for phenylketonuria were obtained in 3, for cystinuria in 2 and for Hartnup disease in 1. The overall frequency of metabolic disorders was 0,6%. It is evident that genetic metabolic disease as detected by current screening procedures makes only a small contribution to the overall burden of mental retardation.