Aminoaciduria and organic aciduria in neurology

AMINOACIDURIA AND ORGANIC ACIDURIA IN NEUROLOGY

AMINOACIDURIA AND ORGANIC ACIDURIA IN NEUROLOGYDR. KOUSHIK MUKHERJEEJUNIOR RESIDENT

1

CATABOLISM OF AMINO ACID IN A GLANCE

WHEN TO SUSPECT IN NEWBORNS

AMINO-ACIDURIA

PHENYL KETONURIA(PKU)Discovery of PKU- an important milestone in the history of medicineDiscovered by Asbjrn Flling, one of the first Norwegian physicians to apply chemical methods to the study of medicine.In 1934, the parents,Borgny and Harry Egeland of two intellectually impaired children approached Flling to ascertain whether the strange musty odour of her childrens urine might be related to their intellectual impairment.He analysed their urine specimen and found phenylpyruvic acid in their urine.

Later Flling subsequently requested urine samples from 430 intellectually impaired patients from a number of local institutions.These eight individuals all presented with a mild complexion (often with eczema), stooping figure with broad shoulders, a spastic gait, and severe intellectual impairment.Family studies of the affected individuals led to the suggestion of an inherited recessive autosomal trait. Dr Flling published his findings and suggested the name imbecillitas phenylpyruvica relating the intellectual impairment to the excreted substance,thereafter renamed phenylketonuria

Abjorn Flling

The Egeland children

classic pku

HYPERPHENYLALANINEMIA CAUSED BYDEFICIENCY OF THE COFACTORTETRAHYDROBIOPTERIN

In affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate) that are excreted in the urine, giving rise to the term phenylketonuria (PKU).The term hyperphenylalaninemia implies lower plasma levels (20 mg/dL), if untreated, invariably results in the development of signs and symptoms of classic PKU.The affected infant is normal at birth. Profound intellectual disability develops gradually if the infant remains untreated. Cognitive delay may not be evident for the first few months. In untreated patients, 50-70% will have an IQ below 35, and 88-90% will have an IQ below 65. Only 2-5% of untreated patients will have normal intelligence.Many patients require institutional care if the condition remains untreated. Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom.

Older untreated children become hyperactive with autistic behaviors, including purposeless hand movements, rhythmic rocking, and athetosis.Neurologic signs include seizures (approximately 25%), spasticity, hyperreflexia, and tremors.Diagnosis is through new born screening in developed countries.In developing countries identification of phenylketones in the urine by ferric chloride may offer a simple test for diagnosis of infants with developmental and neurologic abnormalities.

Neonatal diagnosis of pkuEarly diagnosis of PKU is important because the disease is treatable by dietary means.Newborn with PKU frequently has normal blood levels of phenylalanine (PA) at birthAs the mother clears increased blood PA in her fetus through placenta. So, test performed at birth may show false ve results.

PA begins to be elevated when newborn takes milk (containing proteins) for at least 24 hoursAccordingly, feeding with milk for 48 hours is sufficient to raise the newborn blood PA to levels that can be used for diagnosis.

Neonatal screening of pkuMust be made within one month of birth, if mental retardation is to be prevented.

Screening program for neonate (6 14 days of life) using Guthrie test is performed:

- A disk of a filter paper containing blood from a heel prick is placed on plates impregnated with a microorganism, Bacillus subtilis, which requires phenylalanine for growth, the only source being the blood spot. - The growth of the organism is a positive test.

Test has to be confirmed by measuring blood phenylalanine

Guthrie test

Treatment of classic pkuPrinciples of treatment of PKU

Treatment must begin during first 7-10 days of life to prevent mental retardation.. Treatment aims at maintaining blood phenylalanine levels close to normal range.

Treatment should be continued for many years (at least till age of 8) as high blood levels of phenylalanine between 4 8 years leads to mental retardation. However, life-long treatment by diet restriction of phenylalanine is preferred

Avoiding low levels of phenylalanine in blood as it is an essential amino acid and therefore is essential for physical & mental growth.

Tyrosine is must be supplied in diet as it cannot be synthesized from phenylalanine in cases of PKU

Protocol of treatment:By feeding synthetic amino acid preparations low in phenylalanine Supplemented with some natural foods such as vegetables, fruits & certain cereals selected for their low phenylalanine content & rich in tyrosine.

22

MRI brain of a 27-year-old man who was screened at birth and was found to have a borderline phenylalanine level.

2001 by American Society of Neuroradiology

HYPERPHENYLALANINEMIA CAUSED BYDEFICIENCY OF THE COFACTORTETRAHYDROBIOPTERINIn 1-3% of infants with hyperphenylalaninemia, the defect resides in 1 of the enzymes necessary for production or recycling of the cofactor BH4.If these infants are misdiagnosed as having PKU, they may deteriorate neurologically despite adequate control of plasma phenylalanine.More than half of the reported patients have had a deficiency of 6-pyruvoyltetrahydropterin synthase.Patients with hyperphenylalaninemia as a result of BH4 deficiency also manifest neurologic findings related to deficiencies of the neurotransmitters dopamine and serotonin.

The clinical manifestations differ greatly from PKU.Neurologic symptoms often manifest in the first few months of life and include extrapyramidal signs (choreoathetotic or dystonic limb movements, axial and truncal hypotonia, hypokinesia), feeding difficulties, and autonomic abnormalities. Intellectual disability, seizures, hypersalivation, and swallowing difficulties are also seen. The symptoms are usually progressive and often have a marked diurnal fluctuation.Diagnosd by Measurement of neopterin (oxidative product of dihydroneopterin triphosphate) and biopterin (oxidative product of dihydrobiopterin and BH4) in body fluids, especially urine and BH4 loading test.

The control of hyperphenylalaninemia is important in patients with cofactor deficiency, because high levels of phenylalanine cause intellectual disability and also interfere with the transport of neurotransmitter precursors (tyrosine, tryptophan) into the brain. Plasma phenylalanine should be maintained as close to normal as possible (