Indian Pediatrics 2001; 38: 518-524
Clinical Features of Organic Acidemias: Experience at a Tertiary Care Center in Mumbai
Manuscript received: July 4, 2000;
Organic acidemias are a heterogeneous group of inherited metabolic disorders due to defects in the catabolism of branched-chain amino acids, lysine and disorders that result in accumulation of lactic acid and dicarboxylic acids(1). Individually, these inborn errors of metabolism are rare and infrequently reported worldwide. Their prevalence is probably underestimated since a substantial proportion of cases remain undiagnosed or mis-diagnosed(2). Of 366 patients with inborn errors of metabolism diagnosed over a period of 20 years at the Hôspital des Enfants-Malades, organic acidemias accounted for 27% of the cases, hyperlacticacidemias (including respiratory chain disorders) in 12% and fatty acid oxidation defects in 8.3%. In this series methylmalonic acidemia was the commonest organic acidemia followed by propionic acidemia(3). In another, lactic acidemias were the commonest disorders (18%), followed by propionic acidemia (9.2%), methylmalonic acidemia (8.8%) and multiple carboxylase deficiency (6.6%)(3). Apart from solitary cases of propionic acidemia, biotinidase deficiency, fatty acid oxidation defects and Leighs disease a Medline search over the past 10 years did not disclose other reports from India(4,5). This can be attributed to the lack of awareness of the wide spectrum of manifestations and lack of diagnostic facilities. This study aims to provide an overview of the clinical features and types of organic acidemias diagnosed at a tertiary care center in Mumbai.
This retrospective study was conducted by reviewing records of patients suspected to have organic acidemias over a period of 4 years from January 1995 through December 1998. Demographic data, clinical manifestations, results of biochemical investigations and neuroimaging were recorded. Clinical mani-festations were classified as acute, subacute and chronic based on the duration of symp-toms. Biochemical investigations performed were blood gas analysis; screening tests for mental retardation (ferric chloride, dinitro-phenylhydrazine, cyanide-nitroprusside and Benedict’s test)(6); paper chromatography of aminoacids in urine and plasma; estimation of serum ammonia, lactate, pyruvate and blood sugar and semiquantitative estimation of urine ketones. Lactate level in cerebrospinal fluid was estimated when indicated. Definitive diagnosis was established by gas chromato-graphy and mass spectroscopy (GC-MS) of urine samples for organic acids(2,7).
Inborn errors of metabolism were suspected in 231 patients. The diagnosis of organic acidemias was confirmed in 32 patients in whom results of GC-MS were available. In 24 patients, the mean age at presentation was 12.5 months (range 2-48 months). The remaining 8 were neonates and their clinical characteristics were studied as a separate group. There were 22 boys and 10 girls. Parental consanguinity was found in 11 (34.3%).
Propionic acidemia and respiratory chain disorders seen in 19.3% each were the commonest organic acidemias diagnosed in this series followed by tricarboxylic acid cycle defects in 12.9% and methylmalonic acidemia in 9.6%. Rare disorders detected in this study were glutaric aciduria type I, holocarboxylase synthase deficiency, 3-methylglutaconic acid-uria type X, beta ketothiolase deficiency and carnitine-palmitoyltransferase deficiency with distal renal tubular acidosis (RTA).
In the post neonatal age group (n = 24) symptoms were subacute or chronic; majority presenting like a static encephalopathy with developmental delay, seizures and failure to thrive or neurodegeneration (Table I). The seizures were generalized tonic-clonic in 6 patients and myoclonic in four. A triggering event in the form of an intercurrent febrile respiratory or gastrointestinal illness could be identified in 41% of the patients with acute or recurrent symptoms, most often resulting in permanent neurologic handicap or punctuat-ing an otherwise static encephalopathy. Breathlessness, vomiting, depressed senso-rium and floppiness characterized these periods. All the neonates (n = 8) were sympto-matic in the first week of life with acute symptoms (Table I). Fifty per cent each had breathlessness and seizures as the initial manifestations. Developmental delay was found in 37.5%.
Based on the result of biochemical investigations, patients could be divided into 4 groups. The biochemical abnormalities and the diagnosis in the various groups are shown in Table II. In the older age group predominant lactic acidosis was detected in 42%, pre-dominant ketoacidosis in 33% and acidosis alone in 25%. In the 10 cases with lactic acidosis, lactate: pyruvate ratio was elevated (>30:1) and cerebrospinal fluid lactic acidosis was present in 4. Severe acidosis (pH £7.1) was noted in 5 cases: in 2 patients of propionic acidemia and one each with beta ketothiolase deficiency, Leighs disease and tricarboxylic acid cycle defect. Moderate to severe ketosis was present in 3 cases, two with propionic acidemia and one with beta ketothiolase deficiency. In the neonatal group lactic acidosis and ketosis was present in 37.5% each, while 12.5% each had isolated acidosis or keto-sis. Five neonates with propionic acidemia, methylmalonic acidemia, tricarboxylic acid cycle defect, respiratory chain disorder and carnitine palmitoyltransferase deficiency with distal RTA had severe acidosis. Two neonates with propionic acidemia and methylmalonic acidemia had moderately severe ketosis.
Abnormalities were noted on CT scan and/or MRI in all 22 patients subjected to neuroimaging. The abnormalities included hypomyelination, retarded myelination, cortical atrophy, basal ganglia abnormalities and cerebellar atrophy. MRI in Glutaric aciduria type I was diagnostic and revealed enlarged perirolandic CSF spaces, bilaterally symmetrical signal abnormalities of the basal ganglia and extensive while matter abnor-mality of the cerebral hemispheres.
The overall mortality was 9.3% (neonates 12.5%, older children 8.3%). The management is summarized in Table III. Long-term treatment consisted of dietary modification, carnitine and pharmacological doses of vitamins. Antiepileptic drugs were prescribed when necessary.
Table I__Clinical Manifestations
Table II__Biochemical Abnormalities and Diagnosis
Table III__Acute and Long-term Therapy
Doses: Carnitine 100 mg/kg/day, Biotin 10 mg/day, Riboflavin 200 mg/day, Thiamin 600-1000 mg/day, Metronidazole 10 mg/kg/day intravenous followed by oral administration, Vitamin B12 1mg intramuscular weekly, Baclofen 5mg/kg/d, Levodopa 200 mg/d.
Organic acidemias were suspected in 25% of the total population being evaluated for inborn errors of metabolism. An extensive compilation of inborn errors of metabolism diagnosed at our center from 1978 to 1997 (unpublished data) revealed a prevalence of 3.9% for ogranic acidemias compared to 27% reported elsewhere(3). There is limited data on the prevalence of organic acidemias from different parts of India. A number of patients may die without proper diagnosis, as the disorder is often not suspected.
Organic acidemias are suspected typically in healthy neonates with unexplained meta-bolic or neurological deterioration. Non-specific symptoms such as vomiting, refusal of feeds, failure to thrive, lethargy, breath-lessness, seizures and disturbed consciousness cannot distinguish organic acidemias from a wide variety of medical and surgical emergencies(2). Disorders associated with neutropenia and thrombocytopenia like propionic and methylmalonic acidemia are prone to be mistaken for neonatal sepsis(2,8). A negative "sepsis screen" and bacteriology or paucity of clinical and radiological signs in a breathless neonate is crucial in suspecting the actual diagnosis and undertaking prompt evaluation. Such symptoms resulting from severe acidosis and/or ketosis were the presenting features in 5 neonates. Although acidosis is the hallmark of propionic acidemia, an uncommon biochemical presentation is hyperammonemia without significant acidosis as noted in one of the neonates in our series(8). The dramatic nature of symptoms accounts for a high proportion of neonates amongst patients of organic acidemias (25% in our series).
In 75% of our patients in whom manifestations were subacute or chronic, the presentation was delayed beyond 1 month of age. In the absence of significant metabolic derangement, symptoms of a static encephalo-pathy such as psychomotor retardation, seizures, spasticity or hypotonia are clinically indistinguishable from common entities such as cerebral palsy. In these patients, neuro-imaging hinted at an underlying metabolic disease. Such chronic silent nonmetabolic presentations are not unusual(8,9). Blood lactate levels can be elevated without concomitant metabolic acidosis(10). Relying on a blood gas report without estimating blood lactate may miss the diagnosis of congenital lactic acidemias in this situation. In 29% a febrile illness mimicking acute encephalitis heralded the onset of neurologic symptoms in a previously normal child. Presence of neurological symptoms out of proportion to the trivial febrile infection provided a clue to suspect an underlying metabolic disease. Such a presentation is characteristic of glutaric acidemia type I(2,11).
Organic acidemias are seldom considered in the differential diagnosis of dystonia and choreoathetosis(2,9). Dystonia was noticed in 3 patients with respiratory chain disorder, glutaric acidemia and medium chain acyl- CoA dehydrogenase deficiency. Choreo-athetosis was the presenting feature of 3-methylglutaconic aciduria. An extrapyramidal movement disorder is a hallmark of glutaric acidemia type I(12). Awareness of other rare manifestations such as floppiness, cardiomyo-pathy (fatty acid oxidation defects and respiratory chain disorders), dysmorphisms (propionic acidemia and pyruvate dehydro-genase complex defects) and malformations (corpus callosal hypoplasia or agenesis in pyruvate dehydrogenase complex defects) is lacking. Disorders like propionic, methyl-malonic or isovaleric acidemia, and maple syrup urine disease can masquerade as cerebrovascular accidents or brain tumors when they present with focal signs or with intracranial hemorrhage. Other noteworthy manifestations are recurrent attacks of dehydration, Reye’s-like illness and sudden infant death syndrome(2,8,10,13). Exception-ally, pancreatitis can be the initial manifesta-tion but more often it is a complication of disorders of branched chain amino acids(14). Similarly, interstitial nephritis or chronic renal failure complicating methylmalonic acidemia can manifest with hypertension(15). Fatty acid oxidation defects and fructose metabolic defects may have to be considered in the evaluation of hypoglycemia when the usual causes are ruled out(7). Disorders like holocarboxylase synthase deficiency and biotinidase deficiency manifest with a variety of dermatosis, though commonly these develop secondary to dietary restrictions.
Neuroimaging plays an important role in the evaluation of patients with organic acidemias. Characteristic signal abnormalities and distribution of lesions in diseases such as maple syrup urine disease and glutaric aciduria type 1 can corroborate clinical suspicion and guide the clinician to undertake appropriate investigations(16). A normal neuroimaging would make the diagnosis of an organic aci-demia unlikely(2,11). In developing countries with no access to expensive bio-chemical investigations, neuroimaging along with blood gas analysis, estimation of blood levels of lactate, pyruvate and ammonia and testing urine for ketones are simple tests available to clinicians for the initial screening of suspected cases of organic acidemias. Not only do they suggest the diagnosis, but also provide a basis for the classification of disorders into major groups such as those with ketoacidosis, those with isolated lactic acidosis, those with hypoketotic lactic acidosis and so forth(5).
To summarize, organic acidemias are usually suspected by their acute dramatic manifestations in neonates. In older children, the condition may often remain undiagnosed. Striking acidosis or ketosis need not always be present in older children or in those with episodic disease. Presence of unexplained neurological symptoms whose severity is out of proportion to the inciting illness should arouse suspicion of a metabolic disease. Screening tests like blood gas analysis, estimation of blood levels of lactate, pyruvate and ammonia, urine examination for ketones and neuroimaging provide valuable clues to the presence of an underlying metabolic disease.
The authors thank Professor M. Duran of the University Children’s Hospital, Nether-lands for analyzing urine samples of our patients for organic acids.
Contributors: MM participated in collection and interpretation of data and drafting the paper; she will act as guarantor for the paper. PK was involved in data collection and helping in drafting the paper.
Competing interests: None stated.