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IEMs in Newborns

Common Disorders in Critically Ill newborns

Data of Our Institute

1. Biotinidase Deficiency
2. Glutaric Aciduria Type II
3. Pyridoxine dependent seizures
4. Molybdenum cofactor deficiency
5. Dicarboxylic Acidurias
6. Non Ketotic Hyperglycinemias

1. Biotinidase Deficiency

Biotinidase deficiency

Dr. Anil B. Jalan ,
MD., D.C.H., M.C.P.S.

Abstract :- Note that the neonatal form of this condition is holocarboxylase synthetase deficiency.

Multiple carboxylase is a deficiency of
1. Propionyl Co A carboxylase ,
2. 3 - methyl - crotobyl Co A carboxyles, and
3. Pyruvate carboxylase. ( It is also referred to as biotinidase deficiency. )

It usually presents after the age of 3 months but might manifest as late as 10 years. The skin lesions, mostly a perioral stomatitis or a glossitis, are often diagnosed as acrodermatitis enteropathica, and the hair is sparse. Development is often delayed and later a cerebellar ataxia develops. The patients are intermittently ketoic and the characteristic pattern is an excess excretion of 3 - methylcrotonylglycine, 3 - hydroxyvaleric acid, 3 - hydroxypropionic acid, and 2 - methylcitric acid. Serum biotinidase is reduced.

Introduction :- Biotin is an essential cofactor in the formation of the four carboxylases discussed later in the chapter, acting as prosthetic group for the formation of enzymatically active holocarboxylases from the inactive apoenzyme. Biotin is chiefly derived from dietary sources, but a significant amount is recycled by the biotinyl hydrolase biotinidase. A deficiency of Biotinidase results in a clinical syndrome similar to but usually less severe and later presenting than the holocarboxylase synthetase deficiency phenotype. ( 1 )

Clinical case histories :- We routinely perform Serum Biotinidase levels from blood samples collected at birth or in NICU , especially for critically ill newborns.

Biotinidase :-

1. Normal range :- 4.3 - 7.54 Nmols / min. / ml
2. Partial deficiency :- 2.5 - 4.30 Nmols / min. / ml
3. Deficient :- < 2.5 Nmols / min. / ml

Table No. 1 :- Details of Biotinidase levels in our patient group n = 18

1 B/O R.B. : 0.00 : Deficient : Expired
2 B/O V.B. : 0.70 : Deficient : Expired
3 Baby V.S. : 3.20 : Partial def. : Improved
4 Baba K.S. : 2.10 : Deficient : Expired
5 B/O J.A. : 2.80 : Partial def. : Expired
6 B/O S.M. : 2.70 : Partial def. : Improved
7 B/O R.P. : 0.00 : Deficient : Expired
8 B/O C.M. : 1.70 : Deficient : Improved
9 Baby S.K. : 3.60 : Partial def. : Improved
10 B/O P.S. : 3.40 : Partial def. : Expired
11 B/O S.H. : 3.40 : Partial def. : Improved
12 B/O K.K. : 1.00 : Deficient : Imrpoved
13 Mrs. K.K. : 1.68 : Rx Adv.
14 B/O S.K. : 1.80 : Deficient : Expired
15 Baba A.K. : 3.80 : Partial def. : Improved
16 Baby N.E. : 2.60 : Partial def. : Improved
17 Baba M.S. : 2.70 : Partial def. : Improved
18 Baby D.M. : 0.64 : Deficient : Expired
Discussion :-

The four carboxylases - ( 1 ) .

1. Pyruvate carboxylase ,
2. Propionyl - Co A carboxylase ,
3. 3- methylcrotonyl - Co A carboxylase ,
4. Acetyl - Co A carboxylase -

The above four carboxylases play important roles in :-

1. gluco-neogenesis,
2. fatty acid synthesis, and
3. protein catabolism.

1. Pyruvate carboxylase ( PC ) :- catalyzes the synthesis of oxalo-acetate from pyruvate in the gluco-neogenic pathway.

2. Propionyl - Co A carboxylase ( PCC ) :- converts propionyl - Co A to methylmalonyl - Co A in the catabolic pathway of isoleucine, valine, methionine, threonine, and odd - numbered - chain fatty acids. A defect results in the accmulation of 3 - hydroxy-propionate and methylcitric acid.

3. 3 - methylcrotonyl - Co A carboxylase ( MCC ) :- is involved in the catabolic pathway of leucine , and a defect results in accumulation of the metabolites methylcrotonylglycine , 3 - hydroxyisovalerate, and isovalerylglycine .

4. Acetyl - Co A carboxylase ( ACC ) :- catalyzes the synthesis of malonyl - Co A, which is the first step in fatty acid synthesis .

Defects in any or all of these pathways can cause severe , multisystem metabolic derangement . Isolated deficiencies have been documented for each of the carboxylase , the most common of which is PCC , responsible for propionic aciduria.

The carboxylases PC, PCC, and MCC are mitochondrial enzymes, whereas ACC is a cytosolic enzyme. It is now generally accepted that a functional multiple - carboxylase deficiency can result from either a defect in the holocarboxlase synthetase enzyme ( HCS ), which catalyzes the attachment of biotin to the inactive apoenzyme to form ; the holocarbxylase, or from a defect in biotin recycling caused by a deficiency in the enzyme biotinidase. There is considerable phenotypic heterogeneity , but HCS deficiency is generally the more severe disease with an earlier presentation and more severe sequelae if not recognized early and treated appropriately. Deficiency of both biotinidase and HCS is biotin - responsive.

An inadequate supply of dietary biotin is rarely seen in association with faddish diets containing large amounts of raw egg white. Avidin from egg white binds biotin. Parenteral nutrition without biotin supplementation also results in deficiency . In both cases the clinical picture of multiple carboxylase deficiency is seen .

Phenotype :- There is considerable clinical heterogeneity ; the clinical features most often found in this disorder are listed below. The usual time of onset is after the first year of life. Neonatal or generalized seizures, ataxia, hypotonia, and developmental delay may, individually or in combination, precede other features of biotinidase deficiency. Organic aciduria and metabolic acidosis may not be a prominent feature, making the diagnosis difficult ( 1 ).

Clinical and biochemical features of biotinidase deficiency . ( 3 ) :- Data from analysis of 33 patients .

Feature Occurred at any time

Seizures 22 / 31
Ataxia 18 / 31
Hypotonia 27 / 31
Hyperventilation and / or stridor 6 / 31
Developmental delay 19 / 31
Hearing loss 12 / 29
Ophthalmologic symptoms ( including optic atrophy ) 17 / 31
Skin rash 21 / 31
Alopecia 24 / 31
Candidasis 8 / 31
Metabolic acidosis 25 / 31
Ketolactic acidosis 22 / 28
Hyper-ammonemia 10 / 31
Organic aciduria 25 / 29

Frequency of clinical and Biochemical symptoms in 83 children with Biotinidase deficiency prior to treatment. ( Wolf )

% of affected children Symptoms

A. > 50 % Hair loss ( alopecia )
Developmental delay
Ketolactic aciduria
Skin rash / skin infection

B. 25 - 50 % Ataxia
Hearing loss
Mild hyperammonemia
Respiratory distress
Ophthalmologic problems

C. 10 - 25 % Coma
Feeding difficulties
Fungal infections

D. < 10 % Hepatomegaly
Speech problems

Cardinal clinical features ( 2 ) :-

1. Ataxia
2. Muscular hypotonia
3. Seizures
4. Neuro-sensory abnormalities.
5. Alopecia
6. Periorificial cutaneous eruprtion
7. Other dermatologic manifestations
8. Immuno-deficiencies and repeated infections ( very important cause of death in such infants. )
9. Episodic metabolic acidosis.
10. Lactic acidemia.
11. Metabolites excreted :-

a] 3 - methylcrotonyl glycine
b] 3 - hydroxy iso valeric acid
c] methyl citric acid
d] 3 - hydroxy propionic acid

12. Defective / reduced activity of enzyme Biotinidase in Serum , Plasma , culture skin fibroblasts and Liver.

Clinical features in detail :-

1. Seizures :- Seizures in Biotinidase deficency may be severe and intractable. Infantile spasms may occur without other characteristic symptoms, but most of the patients develop generalized tonic & clonic seizures. Of 78 symptomatic children, 55 % had seizures, which were the presenting feature in 70 % of these cases. In 49 %, the seizures were not well controlled by anticonvulsant therapy, but in the majority of patients ( 75 % ) they were abolished by biotin treatment.

2. E.E.G. :- The EEG is often normal in biotinidase deficiency, although diffuse slowing consistent with a metabolic encephalopathy is frequently seen during the episodes of acute metabolic decompensation.

a. In a review of 78 symptomatic children , EEGs were available for 21 who had had seizures, 16 were abnormal. The initially abnormal EEGs in 8 of 12 infants became normal or improved on Biotin treatment.

b. The EEG was found to be normal in a 26 month old child despite ataxia and language delay.

c. A 23 month old child with marked developmental delay, hypotonia, tonic - clonic seizures, normal plasma but elevated CSF lactate had an EEG that showed diffuse slowing and minimal diffuse convulsive activity. The EEG rapidly normalized with biotin treatment.

d. A 19 - month old female infant with alopecia, eczema, hypotonia, brisk tendon reflexes, and optic atrophy as well as lactic and pyruvic acidemia had excessive slow - wave EEG activity. She also had poorly formed visual evoked potentials ( VEPs ), consitent with marked optic atrophy.

e. A 23 month old infant with hypotonia, sparse hair, labored respirations , and history of generalized convulsions had widespread mild EEG abnormalities but no paroxysmal activity. An ERG ( electro retinogram ) was normal in this child, but VEPs showed reduced amplitude of the early components. There was also severe hearing loss.

f. A 13 year old boy presented with progressive optic atrophy and spastic paraparesis, was studied by positron emission tomography ( PET ) and computed electeroencephalographic topography ( CET ). Prior to treatment, PET scanning showed that the ralative metabolic rate for glucose was more than two SD below the mean for normal controls in the temporal and occipital lobes. Following treatment, these levels normalized. The CET showed asymmetrical slowing in the left temporal and frontal areas before treatment and was normal after treatment. Clinically there was marked improvement in visual acuity, with a milder improvement in the spastic quadraparesis.

g. A clinical syndrome resembling Leigh?syndrome has been described. ( discussed in detail later in this chapter ).

3. Neuro-sensory abnormalities :- involving the optic and auditory nreves have recently been observed in a number of patients with this syndrome.Some patients have had optic atrophy or neuro-sensory hearing loss . Most of the neurologic manifestations of disease disappear in response to treatment with biotin , as do cutaneous features. On the other hand , sensorineural abnormalities involving the optic nerve and auditory nerve may persist for a longer time or may not resolve at all. However there is recent evidence that early treatment with biotin will have favourable outcome even in neurosensory deficits like optic atrophy or hearing deficits.

4. Dermatologic manifestations :- Cutaneous lesions tend to be patcy in older children as against neonates where it is usually a generalised body eruption . They are associated with periorificial cracking lesions and there may be blephero - conjunctivitis of sufficient severity to lead to admission to hospital . Corneal ulceration may occur. Perioral stomatitis is regularly seen and there may be glossitis. Clinical features may resemble acrodermatitis enteropathica. Anhidrotic ectodermal dysplasia has also been considered in this disorder. The eruption may appear seborrheic. The alopecia may be progressive to alopecia totalis but it is usually less than total and may be simple sparseness of cranial hair, eyebrows or eyelashes.

5. Immunodeficiency :- Immunodeficiency has been reported with abnormalities in function of both T and B cells. There may deficiency of Ig A and poor response to immunization. In the clinical setting this may present as recurrent infection , severe infection , septicemia, candidial infections etc. Many such children are known to succumb to infection if not treated with Biotin. Prompt treatment with Biotin is known to reduce the mortality and morbidity. Biotin deficiency in guinea pigs has been associated with decresed numbers of T and B lymphocytes.

Partial Biotinidase deficiency :-

Biotinidase deficiency can appear in a milder form called partial biotinidase deficiency . In this condition the activity of Biotinidase enzyme is about 10 - 30 % of normal activity as compared to < 10 % in the profound or more serious form of this condition. Thus far , all of the children who have been classified as having partial deficiency have been identified through neonatal screening screening programme ( in the wetern world ). Untreated children with partial deficiency are usually healthy , although symptoms have occured in some children when they were stressed from an infection or poor diet. Currently most children with partial deficiency are being treated with biotin, usually slihghtly less ( 2 to 5 mgm / day ) than that used to treat profound deficiency , whereas others remain untreated and are carefully watched for the development of symptoms. The full clinical significance of such partial deficiency is not fully understood.

Multiple carboxylase deficiency involves following enzymes :-

1. Propionyl Co A carboxylase.
2. 3 - methylcrotonyl Co A carboxylase
3. Pyruvate carboxylase
4. Biotinidase

Leigh?syndrome ( 2 ) :- Biotinidase deficiency may present with featres of Leigh?syndrome. Leigh?yndrome infact is a clinical entity with distinctive features and there are three different varieties described in the literature.

Inheritance Metabolic defect Mutation

A Autosomal recessive Cytochrome c oxidase Unknown

NADH dehydrogenase Unknown
Pyruvate carboxylase 11 q 13
Biotinidase 3 q 25
Pyruvate dehydrogenase ( lipo-amide dehydrogenase ) Unknown
B X linked recessive Pyruvate dehydrogenase ( E 1 subunit ). X p 22.2 -22.1
( insertions, deletions, point mutations ) .
C Maternal Mitochondrial Subunit 6 of ATPase NARP 8993
t RNA ( Lys ) MERRF 8344

t RNA ( Leu ) MELAS 3243

Popypeptide ND 6 of NADH dehydrogenase Leber 14459
NARP Neuropathy , ataxia & retinitis pigmentosa .

MERRF Myoclonic epilepsy and ragged red fibres

MELAS Mitochondrial encephalopathy , Lactic acidosis and stroke like episodes.

Clinically three syndromes can be distinguished according to the age of onset.

1. The neonatal form :- presents initially with disorders of sucking and swallowing, and respiratory difficulties ( for example , Ondine?curse ) (Seitz et al , 1984 ). Latter, other symptoms of brainstem dysfunction ( aberrant eye movements, facial weakness ) and severe motor delay are recorded . Death occurs early.

2. The classic infantile form :- presents at an age of less than 2 years and often less than 1 years.

1. Early psychomotor development is usually normal.
2. The early course is usually rapid.
3. Symptoms are made worse by intercurrent infection or a carbohydrate - rich diet.

4. Presenting complaints may include :-

a. progressive psychomotor slowing,
b. weekness,
c. ataxia,
d. feeding and swallowing difficulties,
e. vomiting,
f. poor weight gain,
g. decreased alertness,
h. poor visual fixation,
i. myoclonic jerks, or generalized convulsions ( Pincus , 1972 ).

5. On examination, clinical features that lead to the diagnosis :-

a. Eye findings :- may include nystagmus , strabismus , profound slowing , ptosis, ophthalmoplegia , optic atrophy , and atypical pigementary degenration of the retina ( Sedwick , 1984 ). Retinal pigmentary degeneration is present in about 40 % of cases of maternally inherited Leigh syndrome ( Santorellin , 1994 ) .
b. Other cranial nerve signs may include :- deafness , dysphagia and facial wekness.
c. Other neurologic signs :- less specific neurologic signs may include axial hypotonia, spasticity , dystonia , choreoathetoid movements , and varying degrees of ataxia ( campistol 1986 ). Deep tendon reflexes may be increased or decreased.
d. Respiratory irregularities :- a central hyperventilation and hypoventilation syndrome, or central apnea are remarkable.
e. Some patients are unusually hirsute.
f. Other occassional features include cardiomyopathy and the renal de Toni - Franconi - Debre syndrome of tubular renal acidosis.
g. Death is the final outcome, often occuring rapidly, within the course of a few weeks or months.
h. However, remissions followed by further exacerbations are sometimes seen, and the child may live for several years.

3. A rare juvenile from :- of the disease has also been described ( Grunnet et al, 1991 ). The course of the illness is often characterized by an insidious onset in childhood, leading to neurologic defects, such as :-

a. mild spastic paraparesis,
b. ataxia,
c. exercise intolerance,
d. nystagmus,
e. visual impairment, and
f. Parkinson - like features.
g. Children with Leigh syndrome are usually below normal in weight and height.
h. After a long quiescent period, the illness terminates acutely or subacutely during the second decade.
i. The terminal stage is characterized by a rapid deterioration to coma and marked respiratory depression .

The results of electrophysiologic studies change with time and vary from patient to patient. Motor nerve conductions velocities may be slow. EEG may show a generalized slowing of background activity, sometimes superimposed by epileptogenic features. Brainstem auditory evoked potentials and visual evoked potentials may be abnormal. The ERG may suggest diffuse retinal dysfunction .

Neuroradiologic investigations are particularly helpful in the diagnosis of Leigh syndrome. Cranial MRI is much more sensitive in detecting lesions than CT.

Hyperintensive lesions on T2 weighted images involving symmetrically the basal ganglia and brainstem, with predominant involvement of the putamen are highly suggestive of Leigh syndrome. Abnormalities of the subcrtical white matter can occur .

Neuroimaging studies in Biotinidase deficiency ( 1 ) :-

&#61623; Neuroimaging studies show considerable variability.

&#61623; A single report of basal ganglia calcification in the absence of expected clinical symptoms was reported in a 26 month old infant with Biotinidase deficiency. Calcifications on CT brain scan were punctate and diffuse. The MRI scan showed mild heterogenity in the cerebral white matter on T 2 weighted images, which was interpreted as being within the range of normal.

&#61623; A 2 month old boy developed myoclonic seizures at the age of 2 months, which continued intermittently for another 3 months. He showed developmental delay and at the age of 17 months had an episode of metabolic acidosis and Lactic acidemia associated with respiratory distress, pneumonia, and hair loss. Organic acid analysis and biotinidase assay confirmed the diagnosis. A CT scan brain at the age of 2 months of age, at the onset of symptoms showed difuse white matter leucencies, interpreted as delayed myelination. At 13 month , the CT scan showed mild cerebral atrophy. At 17 months during the acute metabolic decompensation, an MRI showed diffuse brain atrophy ; 10 months later , following biotin treatment , an MRI scan showed normal brain size and white matter, with resolution of previous atrophic changes. At 6 years of age he was developmentally normal but had moderate hearing loss.

&#61623; Another infant developed myoclonic seizures at the age of 2 months. A CT scan showed normal brain structure and mild decrease of white matter density over frontal regions . At 6.5 months, she had marked alopecia and eczema, hypotonia, and intermittent seizure activity with an abnormal EEG. The CT scan showed diffuse atrophy. After treatment with biotin, clinical symptoms resolved, apart from bilateral sensorineural hearing loss. A repeat CT scan at 13.5 months was normal. At 5 years 4 months , she had persistent hearing loss , and an overall developmental age of 3 - 4 years.

Human and rat brains both have much lower biotin levels than serum or other tisues, which may be the result of inefficient recycling of biotin as biotinidase enzyme activity is also low. Ths would make the brain more dependent on transfer of biotin than other tissues and thus more suceptible to deficiency. Several reports document the preferantial elevation of lactate and pyruvate in the CSF in patients with neurologic symptoms, even in the absence of systemic lactic acidosis, suggesting that pyruvate carboxylase is predominantly affected by biotinidase deficiency in the brain. Much of the neurologic symptomatology may be due to the toxic effect of local accumulation of lactate and organic acids. ( 1 )

Biocytin a conjugate of biotin that accumulates in biotinidase deficiency, even in the presence of biotin supplementation, has also been suggested as a toxic metabolite. It may be competing with biotin as a substarte for holocarboxylase synthesis, and this may explain why progression of symptoms can be seen in some patients. ( 1 )

Diagnosis of Biotinidase enzyme deficiency :-

1. Enzyme assay :- Diagnosis if confirmed by assay of biotinidase enzyme activity in plasma or serum , independent of biotin supplementation. Levels can be measured in cultured fibroblasts or liver . The usual method measures the cleavage of the artificial substarte N - biotinyl - 3 aminobenzoate or the natural substarte.

2. Plasma levels :- of Lactic acid , Pyruvic acid and alanine are elevated. So also CSF lactate and pyruvate may be elevated despite normal plasma levels.

3. Organic aciduria pattern :- Characteristic organic aciduria is usually present, especially in the established cases, it can be detected by Gas Chromatography with Mas Spectrometry of Tandem Mass Spectrometry.

a. Lactic aciduria
b. 3 - hydroxy isovaleric aciduria
c. 3 - hydroxypropionic aciduria.
d. methyl citric aciduria.
e. 3 - methylcrotonylglycinuria.

4.Muscle and Skin biopsy :- Muscle and skin biopsies are often necessary to establish the biochemical diagnosis. Pyruvate carboxylase and pyruvate dehydrogensase activity are best measured in tissue fibroblasts. At the time of muscle biopsy , histochemistry , electron microscopy and oxidative phosphorylation enzymology should be performed in cases of suspected Leigh?syndrome, besides the study of Biotinidase enzyme. Ragged red fibres or striated muscles are almost never identified by light microscopy. Ultrastructural examination frequently shows discrete mitochondrial changes , such as increased size , bizzare shape and disoriented cristae ( Wyatt 1987 ). Mitochondria should be immediately isolated for oxidative phosphorykation histochemistry. Muscle biopsy should be screened for the most common mitochondrial DNA point mutations ( associated with NARP , MELAS , and MERRF ) and mitochondrial DNA depletion.

Prenatal diagnosis and neonatal screening :- Prenatal diagnosis is possible by asaying biotinidase activity in the amniocytes.

Newborn screening :- Newborn screening can be achieved utilizing dried blood on filter paper but has not been widely instituted due to the relatively low incidence of the disorder in USA (1 in 60,000 ). Early detection and treatment with supplemental biotin, 10 mgm / day, is essential to prevent severe neurologic and metabolic sequale. Treatment results in reversal or amelioration of symptoms in most cases.

Incidence :-

Countries where Biotinidase is included in newborn screening 1 : population
1 Brazil 1 : 112,752

2 New Zealand 1 : 91,400

3 U.S.A. 1 : 60,000

We personally donot recommend the routine screening of Biotinidase in newborns, since the incidence is not as high as other disorders included in Neonatal Screening Programme. However we also recommed the use of biotinidase enzyme assay in all the critically ill newborns and infants , infants and children with neurological manifestations , especially when associated with plasma or CSF lactta elevation. Facility for the enzyme assay must be available at one central lab. Biotinidase deficiency is one of the treatasble IEM and the benefit of early detection and treatment should not be denied to any patient only on the grounds of rarity amongst general population. From the list of our 20 patients, who were sick newborns or children with neurologic manifestations, it is obvious that we had 4 patients of which 3 expired. The incidence comes to nerly 5 % which is much higher than the general population incidence of 0.00166 %. We shall further recommend that pending the report of Biotinidase enzyme, any sick newborn with elevated Lactic acid must be given Biotin 10 mgm / day. This dose can be modified later on or even omitted. Supplementing biotin without the confirmed report will not harm the baby even if it is given for a long period.

Biochemistry , Molecular Biology , and Genetics :- The biotin cleavage system is illustrated in Fig. 1. The holocarboxylases are degraded in lysosomes to biocytin or short biotinyl peptides , which are then cleaved by biotinidase to release free biotin , allowing the synthesis of the holocarboxylase from the apocarboxylases , thus continuing the cycle . A deficiency of biotinidase results eventually in a functional deficiency of the four carboxylases and, therefore , a biochemical profile the same as that found in HCS deficiency . The molecular characterstics of biotinidase deficiency have not yet ben determined . The disorder is inherited as an autosomal recessive trait . Heterozygotes have intermediate biotinidase activity .

Treatment :- Patients are effectively treated with relatively low doses of biotin. The dose most commonly employed is 10 mgm / day, but as little as 5 mgm / day has been effective in controlling this disease. The organic aciduria and virtually all the clinical manifestations of the disease disappear promtly after the initiation of the treatment. However the auditory and optic nerve losses may not recover completely ( 1 ) .

Pre-symptomatic treament in a patient diagnosed by assay of cord blood because of the disease had previously been diagnosed in a sibling has been followed by completely normal development, including vision and hearing for at least 14 months. In one patient oral and cutaneous administration of unsaturated fatty acids was followed by remissions of alopecia and cutaneous lesions, suggesting that a deficiency of Acetyl Co A carboxylase required for fatty acid synthesis might be involved in the pathogenesis of these manifestations ( 1 ) .

Referrances :-

1. Michael Baraitser , The Genetics of Neurology Disorders , 3rd Edition, Oxford Monographs On Molecular Genetic - 34 , 223 - 224
2. Bruce O. Berg , Principles of Child Neurology , International Edition , Pg 1063 - 1068 .
3. Ronald B. David , Child and Adolescent Neurology , Mosby?Neurology - Psychiatry Accesseries, Pg 322 - 324.
4. William O Nyhan, Nadia Sakati , Diagnostic Recognition of Genetic Diseases , ( 1987 ), Pg.
5. Wolf B. Heard GS, Weissbecker KA , , Biotinidase deficiency : Initial Clinical Features and rapid diagnosis. Ann. Neurology 18 : 614 - 617 , 1985.

Click here for OMIM description of Biotinidase Deficiency

Click here for OMIM description of Biotin Responsive Multiple Carboxylase deficiency

2. Glutaric Aciduria Type II

Click here for further description of Glutaric Aciduria Type II A ( OMIM )

Click here for further description of Glutaric Aciduria Type II c ( OMIM )

( Erhylmalonic - adipic aciduria ; Multiple acyl Co - A dehydrogenase deficiency )
Often a paediatrician or a gynecologist comes across a case where there have been unexplained neonatal deaths mostly or exclusively of males. It is a common observation that in India most of the families would go to any extent to concieve a male child. When such a history ( of repeated male neonatal deaths ) is available the prenatal diagnosis and management becomes rather difficult. When the fetus is identified as a male child, the obvious psychological pressure starts building up. Parents would like to continue with the pregnancy but there are all the chances , that such a neonate may face the same problems and my succumb to the metabolic diagnosis in the index case. We would advice to collect blood , urine, CSF etc. even after death of a neonate as this will definately help in future pregnancy.

Cardinal clinical features :-

1. Affecting mostly males
2. Overwhelming neonatal illness
3. Macrocephaly
4. Genital anomalies
5. Undescended tests
6. Hypospadias
7. Chordee
8. Respiratory distress
9. Convulsions
10. Early death
11. Metabolic acidosis
12. Acid or sweaty feet odour
13. Aliphatic mono and dicarboxylic acids and sarcosine and glycine conjugates accumulate in blood and urine.
14. Altered function of electron transfer flavoprotein ( ETF ) or ETF - ubiquinone oxidoreductae ( EFT - dehydrogenase ) has been demmonstrated .
15. Mutations in the alpha subunit ( Indo 1991 ; Freeaus 1992 ) and beta subunit ( colombo 1994 ) of EFT has been demonstrated.
16. Although original reports suggested X linked recessive inheritance, the findings of mutations in the EFT subunits demonstrate two loci at 15 q 23 - q 25 and 19 q 13.3 the condition is autosomal recessive.

17. Some dysmorphic features also may be seen :-

a. Low set malrotated ears
b. Epicanthal folds
c. Disproportionately large head
d. High forehead
e. Depressed nasal bridge
f. Short anteverted nose
g. A single transverse palmar crease.
h. Poly cystic kidney - small cysts in the cortex and medulla of the kidney
i. Interventricular septal defect
j. Fat in the heart and liver
k. Symmetrical hypoplasia of temporal lobes
l. Disturbace of gyral pattern with warty protrusions in the brain
m. Bile duct hypoplasia may occur.

1. Hypoglycemia
2. Hyperammonemia
3. Massive urinary excretion of many orgnic acids

a ) Lactic acid
b ) Glutaric acid
c ) Ethyl malonic acid
d ) Adipic acid
e ) Subacic acid
f ) Unsaturated suberic acid
g ) Alfa hydroxy butyric acid
h ) p - hydroxy phenyl - lactic acid
i ) Alfa hydroxy glutaric acid
j ) Alfa hydroxy isovaleric acid
k ) Alfa hydroxy isocaproic acid

4. Increased concentration of other orgnic acids in blood

a ) Ethyl malonic acid
b ) Butyric acid
c ) Methyl butyric acid
d ) Iso butyric acid
e ) Iso valeric acid

Volatile acids are also increased in plasma , demonstrated by GLC and the values are 60 to 4,800 times higher than normal. ( Isovaleric acid , acetic acid , isobutyric acid , alfa methyl butyric acid , butyric acid , & propionic acid ).

5. The concentrations of certain aminoacids is also high in plasma and urine :-

a ) Citrulline
b ) Lysine
c ) Ornithine
d ) Proline
e ) Arginine ( in urine )

The severity of illness is indicated by the fact that all the patients recorded have dies, most of them within first 90 hrs. of birht.

Usually the acidosis is very severe and doesnot respond to sodabicarb therapy. A very disagreeable sweaty feet odour is usually obvious.

This condition is presumed to be X linked recessive disorder but it could be Autosomal recessive also. As of today there is treatment available. During acute illness peritoneal dialysis of exchange transfusion may help to sme extent but the ultimate outcome reported is same for all the cases, that is death ! A trial Riboflavin has been indicated.

The discussion of basic metabolic defect is out of the scope of this book and I would suggest the interested readers to refer Scriver or Nhyan for excellent discusson on metabolic pathways and blocks etc.

2. Pyridoxin dependent seizures :-

Pyridoxine dependent seizures is one of the few inherited metabolic diseases in which seizures are particularly prominent and severe in the absence of any other significant clinical abnormality. affected infants characteristically present very early , in the first few hours or days of life , with intractible , generalized , toinc - clonic seizures and associated EEG abnormalities. On direct questioning , the mother of the infant will often report that she was aware of paroxysms of fetal movement later in the course of the pregnancy. These have been interpreted to be intrauterine conulsions. Apart from the seizures, affected infant appear normal, through failure to control teh convulsions invariably results in hte ultimate development of moderately sever mental retardation. The most remarkable feature of this condiion, which may be the result of a defect in glutamic acid decarboxylase , is its dreamatic response to administration of vitamin B6 ( pyridoxine ).The intravenous administration of 100 mg of the vitamin resuls in prompt cessation of the seizrues and normalization of the EEG abnormalities.

3. Molybdenum cofactor deficiency ( sulfite oxidase / xanthine oxidase deficiency )The development within, the frst week or two of teh birt , of intractible tonic - clonic seizures in an encephalopathy infnat without hypoglycemia , hypocalcemia, hyperammonemia , or significant metabolic acidosis, is suggestiv of molybdenum cofactor deficiency, or the rare disorder, isolated sulfite oxidase deficiency. Imaging studies may show early cerebral hydrocephalus ex vacuo, and signs of hypomyelination of white matter. The presence of evidence of cerebral dysgenesis suggests that considerable damage occurs before birth.

Molybdenum cofactor deficiency is associated with combined deficiency of the two molybdenum - dependent enzymes, xanthine oxidase and sulfite oxidase. The clinical and pathological abnormalities in isolated sulfite oxidase defiicency and indistinguishable from the changes in molybdenum cofactor deficiency. The deficiency of xanthine oxidase causes marked depression of plasma uric acid levels an important and easily acessible clue to the underlying disorder. Urine amino acid analysis shows the presence of increased levels of S - sulfocysteine . However, the diagnosis can often be made at the bedside by tests of the urine for the presence of sulfite using commercially available dipsticks ( Merchoquant 10013 Sulfit Test ).The urine must be fresh because sulfite is oxidized repidly in air at rood temperature . The disease is almost always associated with severe brain damage and deathin early childhood. Survival beyond two years of age is often, though not always , associated with the development of dislocation of the occular lens.

Non Ketotic Hyperglycinemia

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