Gluten Sensitive Enteropathy As A Cause Of Hartnup's Disease
V Raghesh, R Pai
Citation
V Raghesh, R Pai. Gluten Sensitive Enteropathy As A Cause Of Hartnup's Disease. The Internet Journal of Family Practice. 2005 Volume 4 Number 2.
Abstract
This clinical case report shows that Coeliac disease can lead to Hartunp's Disease. This report calls for the simultaneous screening of coeliac disease in patients being tested for Hartnup's disease. There is scope for further research on the relation between coeliac disease and Hartnup's disease and the genetic associations between the two conditions.
Introduction
Hartunp's disease was first identified in 1950's in the Hartnup's family in London. Hartnup's disease is an autosomal recessive disorder due to defective transport of Neutral aminoacids( monoamino monocarboxylic ) in the small intestine and kidneys. Patients usually present with skin lesions, cerebellar ataxia and gross amino aciduria.Heterozygotes are normal. Consanguinity is common. The causative gene is on chromosome 11q 13. It is a sodium dependant and chloride independent neutral amino acid transporter seen predominantly in kidneys and intestine. It occurs when a person inherits 2 recessive genes for the disease –one from each parent. Hartnup's disease has a prevalence rate of one per 24,000 population and is one of the most common amino acid disorders in humans. Levy etal 1 found that incidence of Hartnups' disease is one per 14,219 live births in Massachusetts. The main cause of morbidity in Hartnup's is malnutrition. There is no racial or sexual predilection. Most children with Hartunp's remain asymptomatic. In United States, the disease usually does not manifest because the diet is rich in essential amino acids. Physical examination findings include vesciculo bullous lesions, photosensitivity and hyper pigmentation. The precipitating factors include malnutrition, emotional stress, infections, pyrexia and drugs like sulphonamides.
There will be signs of niacin deficiency like glossitis and gingivitis. There may be episodes of diarrhoea before or after the attacks. Short stature may also be seen Wilcken etal 2 .
Clinical history
A 19 year old short statured girl presents with intermittent cerebellar ataxia, wide based gait,headache and tremulousness with associated double vision since the last four months. Two weeks before she had four attacks of diarrhoea. Her CNS symptoms have been progressively increasing since then. There was a history of skin reddening on exposure to sunlight. Her sister was diagnosed with coeliac disease at the age of 20. She also gave a history of migrane and personality changes.
Family History
C- coeliac disease positive
H- hartnup's disease positive
Clinical examination -positive findings
Areas of hyper pigmentation and red scaly patches were seen in the peri orbital region.
Chronic eczematous changes were seen on the dorsal aspect of forearm and forehead.
CNS examinations revealed cerebellar ataxia, wide gait and intentional tremors.
The Clinical Problem
Hartunp's disease was first identified in 1950's in the Hartnup's family in London. Hartnup's disease is an autosomal recessive disorder due to defective transport of Neutral aminoacids( monoamino monocarboxylic ) in the small intestine and kidneys.Patients usually present with skin lesions, cerebellar ataxia and gross amino aciduria.Heterozygotes are normal. Consanguinity is common. The causative gene is on chromosome 11q 13. It is a sodium dependant and chloride independent neutral amino acid transporter seen predominantly in kidneys and intestine. It occurs when a person inherits 2 recessive genes for the disease –one from each parent. Hartnup's disease has a prevalence rate of one per 24,000 population and is one of the most common amino acid disorders in humans. Levy etal 1 found that incidence of Hartnups' disease is one per 14,219 live births in Massachussets. The main cause of morbidity in Hartnup's is malnutrition. There is no racial or sexual predilection. Most children with Hartunp's remain asymptomatic. In United States, the disease usually does not manifest because the diet is rich in essential amino acids. Physical examination
findings include vesciculo bullous lesions, photosensitivity and hyper pigmentation. The precipitating factors include malnutrition, emotional stress, infections, pyrexia and drugs like sulphonamides.
There will be signs of niacin deficiency like glossitis and gingivitis. There may be episodes of diarrhoea before or after the attacks. Short stature may also be seen Wilcken etal 2 .
Pathophysiology
The disease is caused by failure of transport of tryptophan and other neutral amino acids in the intestine and kidneys. The retained amino acids within the intestine are converted to indolic compounds which are toxic to the neural tissue.
Following absorption, the indolic compounds formed from tryptophan are converted to 3-hydroxy indole (indican) in the liver where it undergoes conjugation with glucoronic acid and subsequently is excreted through the kidneys causing indicanuria. Other degradation products like serotonin and kynurenine are also found in the urine. Since there is a defect in tubular amino acid transport, there is gross amino aciduria. Due to the abnormality in tryptophan metabolism, there may be niacin deficiency which causes pellagra like symptoms. There may be deficiency of glutamine, phenyl alanine, leucine, isoleucine, threonine and histidine. The 2 tissue specific forms of Hartnup's disease was described by Scriver et al (2).
The Differential Diagnosis To Be Considered
Skin rash
Xeroderma pigmentosum, Carcinoid syndrome,Seborrhoeic eczema, Pellagra, SLE, Cockayne syndrome, Infantile atopic eczema ,Pityriasis alba, Hydroa Vaccini forme
CNS
Ataxia telangiectasia-May cause difficulty in diagnosis if there is only mild skin involvement. SLE- can cause diagnostic difficulty if there is photosensitivity with neuro physchiatric symptoms. Leigh's disease, Refsum's disease, Krabbe's disease, Vitamin B 12 deficiency, Niemann Pick disease type C, Tay sach's disease.
Diagnostic Workup
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Positive tryptophan loading test.
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Plasma aminoacid levels normal.
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Urinary indican positive (common to both coeliac and hartnup's)
Management Protocol Adopted
Results
The patient improved constantly with the above management and in course of time became totally asymptomatic. CNS symptoms were totally reversed and there were no fresh skin lesions or photosensitivity rashes or areas or hyperpigmentation.
Urinary chromatography was within normal limits and indicanuria was negative. Slow tapering of Nicotinamide was done and stopped over four weeks. Patient was advised to continue high protein gluten free diet.
Summary and Conclusion
The patient who presented to the outpatient department with symptoms of dermatitis and nervous system symptoms without any history of dietary deficiency of niacin was screened for amino aciduria and indicanuria and a primary diagnosis was made as that of Hartnup's disease. With a positive history of coeliac disease in the family, it was decided to carry out an endomysial antibody test which turned out to be positive. Treatment was started immediately and the patient was put on a high protein gluten free diet and precautions to avoid photo toxicity. Nicotinamide was given and gradually withdrawn over 2 months. The patient's symptoms and signs improved constantly with the therapy and continued to be so even after tapering the Nicotinamide therapy. The patient still continues to be symptom free with diet modification and is carefully monitored for signs and symptoms of Hartnup's disease. Now, after 4months of discontinuing Nicotinamide the patient continues to be totally symptom free and all her investigations are within normal limits.
Areas of Concern
Both Hartnup's disease and coeliac disease are genetically linked although they appear to be mutations in different chromosomes and differ in their patterns of inheritance. This patient with Hartnup's disease turned out to be a case of undiagnosed coeliac disease.It is suggested that all patients with Hartnup's disease be screened for coeliac disease with anti endomysial antibody test as it may be a case of misdiagnosis. Also the family members are to be screened for both the diseases as it is totally controllable with diet modification and moderate drug therapy.
Suggestions for the Future
This report calls for the simultaneous screening of coeliac disease in patients being tested for Hartnup's disease. There is scope for further research on the relation between coeliac disease and Hartnup's disease and the genetic associations between the two conditions.