Clinical manifestations

Presentation and course

HMG-CoA lyase deficiency is characterized by life-threatening metabolic derangement with hypoketotic hypoglycemia and metabolic acidosis. Lethargy, vomiting, tachypnea, hyperammonemia, and moderate hepatomegaly with elevated serum transaminases and lactate values are frequent findings. Grünert and Sass performed a systematic literature review to identify all published cases (14). They analyzed 211 individuals for whom relevant clinical data were available. More than 95% presented with acute metabolic decompensation. Most patients manifested symptoms within the first year of life (42.4% as newborns), whereas very few individuals remained asymptomatic. The neurologic long-term outcome was favorable, with 62.6% of patients showing normal development. Metabolic decompensations can be prompted by catabolic situations resulting in protein breakdown and increased ketogenesis, such as the fetal-neonatal transition, fasting, infections, and excessive protein intake resulting in an increased leucine load.

Between episodes of metabolic decompensation, patients often appear normal. However, residual neurologic deficits caused during metabolic decompensation may be severe.

Several individuals with HMG-CoA lyase deficiency have white matter abnormalities (13; 38). The combination of multifocal severe white matter abnormalities on a background of a diffuse and mild signal abnormality of almost the entire cerebral white matter has been considered unique. Strikingly, even in clinically normal patients, extensive white matter abnormalities can be observed (38).

Cerebral infarction/stroke-like encephalopathy and pancreatitis have been noted as complications in HMG-CoA lyase deficiency (40; 17; 26). Dilated cardiomyopathy has been reported in a 7-month-old boy (with a fatal course) and in a 23-year-old man (12; 21). A girl with this metabolic disease in association with retinitis pigmentosa and intellectual impairment has also been reported (18).

This metabolic disease has also been diagnosed in a 36-year-old woman with a history of recurrent episodes of somnolence and hypoglycemia starting at day 3 after birth (04). She suffered from seizures, a mild right-sided spastic hemiparesis, cerebellar ataxia, tremor, and mild dysarthria. Her IQ values were 60 or lower, and she received special education intervention. A 29-year-old Portuguese man with no prior indication of HMG-CoA lyase deficiency in the medical history has been described as an adult-onset case of this disease (30). A 54-year-old female presented with cervical dystonia and head tremor from the age of 48 years (05). Her past medical history included an unexplained coma episode for 3 days at the age of 3 years, followed by childhood epilepsy.

Prognosis and complications

As with many other organic acidurias, early diagnosis and initiation of appropriate treatment are essential, but not sufficient, for a good outcome in HMG-CoA lyase deficiency. Although some patients have died during metabolic decompensations, with appropriate treatment, most individuals recover from their initial metabolic crisis. A number of patients suffer from neurologic sequelae, including seizures, hemiparesis, and cognitive impairment; dilated cardiomyopathy has been reported twice. Pancreatitis is another well-known complication. However, long-term follow-up information is limited.

Clinical vignette

The first reported patient with HMG-CoA lyase deficiency (09) presented at 7 months of age. During a gastrointestinal illness with diarrhea and vomiting the boy developed lethargy, pallor and dehydration as well as cyanosis and apnea. Metabolic acidosis and hypoglycemia were noted, and Reye syndrome was suspected. Urinary organic acid analysis revealed highly elevated concentrations of 3-hydroxy-iso-valeric, 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids. The patient recovered completely after intensive care and several days of intravenous fluids. At the age of 10 years, he was considered healthy on a self-regulated diet high in potatoes and citrus cordials (45). However, the boy lacked attention at school, required special teaching, and has broken both arms a total of nine times. Occasional attacks of lethargy, pallor, nausea, and vomiting were managed by supplementing glucose intake.

Biological basis

Etiology and pathogenesis

HMG-CoA lyase (EC 4.1.3.4) is a mitochondrial enzyme involved in leucine catabolism. It is expressed in all tissues studied (23). In the liver, HMG-CoA lyase also catalyzes the final step of ketogenesis, the formation of acetoacetate and acetyl-CoA from HMG-CoA. Although the brain cannot use fatty acids directly for energy when glucose levels become compromised, acetoacetate and its reduction product 3-hydroxybutyric acid can provide about 2/3 of the brain’s energy requirements during periods of prolonged fasting and starvation (19). Another role for ketone bodies in the brain is the provision of substrates for the synthesis of molecules such as cholesterol in myelin (25).

Pathophysiology. The deficiency of HMG-CoA lyase may result in a lack of energy and the accumulation of HMG-CoA. The latter may result in increased concentrations of alternative metabolites, including upstream catabolites in leucine degradation. This is reflected by the distinctive pattern of leucine metabolites in urinary organic acids, including elevated 3-hydroxy-3-methylglutaric, 3-hydroxy-iso-valeric, 3-methylglutaconic and 3-methylglutaric acids. Especially during episodes of metabolic decompensation, 3-methylcrotonylglycine and elevated concentrations of several dicarboxylic acids (glutaric, adipic, sebacic, and suberic acids) can also be present in increased concentrations. Notably, although hypoketotic hypoglycemia is typical for HMG-CoA lyase deficiency, ketone bodies may still be detectable in the urine by gas-chromatography with mass-selective detection. In blood, C5-hydroxyacylcarnitine and C6-dicarboxylic monocarnitine are metabolites that can be of diagnostic value. Secondary deficiency of free carnitine may occur. Václavík and colleagues have identified diagnostic biomarkers or HMG-CoA lyase deficiency and have applied them using dried blood spots as they are used in neonatal screening (37).

Increased dietary intake of fat or leucine and a catabolic state result in increased oxidation of endogenous fatty acids and protein and may trigger a metabolic decompensation in HMG-CoA lyase deficiency.

The precise mechanism by which accumulating metabolites contribute to the disease’s course is unknown. It has been reported that the pancreas is, after the liver, the tissue with most HMG-CoA lyase activity (29). This has prompted the authors to suggest that pancreatitis should be considered as a possible complication in HMG-CoA lyase deficiency, especially during acute decompensations.

Genetics. HMG-CoA lyase deficiency is an autosomal recessive disorder due to mutations in the HMGCL gene on human chromosome 1 (24). There is no genotype-phenotype correlation in HMG-CoA lyase deficiency; residual deficiency of HMG-CoA lyase alone does not determine the clinical manifestation (23). Afadhel and colleagues have presented a retrospective study of 62 Saudi individuals with HMG-CoA lyase deficiency from 54 different families, with a HMGCL founder variant (c.122G> A; p.[Arg41Gln]), in the majority of the cases (01).

The crystal structure of the human enzyme provides a useful model for the decrease in HMG-CoA lyase activity associated with pathologic mutations that affect active site function or enzyme stability (11).

Epidemiology

HMG-CoA lyase deficiency is a rare disease with slightly more than 200 patients known (14). Affected individuals represent many different ethnic origins (15; 14). Notably, HMG-CoA lyase deficiency is frequent in Saudi Arabia and in the Portuguese population, where two mutations (122G> A and 109G> A) have been identified in 87% and 94% of the patients, respectively (27).

Prevention

This genetic disease cannot be prevented. However, complications can probably be minimized by early diagnosis and appropriate treatment, including avoidance of prolonged fasting. In some countries HMG-CoA lyase deficiency is a target of general newborn screening, although many affected individuals may already be symptomatic when the results are received (15).

Differential diagnosis

Differential diagnoses include inborn errors of fatty acid oxidation and other organic acidurias that present with metabolic acidosis and lethargy. Hypoglycemia without elevated ketonemia/ketonuria is a typical finding during metabolic decompensation. Abnormalities in the pattern of urinary organic acids include an elevated concentration of 3-hydroxy-3-methylglutaric acid and other metabolites that distinguish this condition from other causes of methylglutaconic aciduria, including 3-methylglutaconyl-CoA hydratase deficiency (41). HMG-CoA lyase deficiency causes a distinctive pattern of urinary organic acids and should provide clarification if potential analytical pitfalls are considered (22). However, 3-hydroxy-3-methylglutaric aciduria has also been reported in at least five individuals with normal activity of HMG-CoA lyase (02; 36; 16; 31). Such reports emphasize the importance of performing enzymatic activity tests in the confirmation of HMG-CoA lyase deficiency.

Diagnostic workup

Usually the clinical examination does not reveal specific indications for HMG-CoA lyase deficiency. However, cerebral magnetic resonance imaging may show abnormalities even in asymptomatic individuals (38). Basic laboratory studies should include a complete blood count, blood gas analysis, determinations of lactate, glucose, electrolytes, transaminases, amylase, lipase, and uric acid in blood. If available, assessment of free fatty acids and ketone bodies in serum can help identify hypoketotic hypoglycemia. Urine should be tested for glucose, protein, and ketones.

The assessment of urine organic acids, free carnitine, and acylcarnitines in blood plays a key role in diagnosing HMG-CoA lyase deficiency. If metabolite profiles suggest HMG-CoA lyase deficiency, confirmation by enzyme assays in cultured skin fibroblasts, leukocytes, thrombocytes, and mutation analysis in the HMGCL gene should be considered.

Management

In the acute decompensation, correction of hypoglycemia by administration of glucose (intravenously, if oral treatment is not feasible) is essential. Management of acidosis by administration of fluids, bicarbonate, and respiratory support, and seizure control are also important. Protein (leucine) and fat should be avoided during metabolic crises.

For maintenance therapy, a low-protein diet enriched with amino acid formula available for patients with maple syrup disease and supplemented with valine and isoleucine are usually recommended. Fat restriction has also been suggested. Fasting should be avoided because it will lead to upregulation of fatty acid oxidation with subsequent hypoglycemia and hypoketosis.

L-carnitine is often administered to prevent secondary carnitine deficiency and to improve renal elimination of presumably toxic leucine metabolites. However, its benefit has not been assessed in a controlled study. Notably, metabolically stable individuals with proven HMG-CoA lyase deficiency are known who followed a self-imposed dietary restriction of fat and protein (03; 18).

An Australian group has reported practice guidelines based on their experience with patients with HMG-CoA lyase deficiency (35).

Special considerations

Pregnancy

Seven pregnancies in four women with HMG-CoA lyase deficiency have been reported (20; 28; 32). Only four pregnancies resulted in the birth of a healthy child at full term, whereas two pregnancies led to spontaneous abortion and one in addition to maternal death. Several case reports have been published on prenatal diagnosis in HMG-CoA lyase deficiency (08; 39; 06; 07). However, information on sensitivity and specificity of the applied methods is unavailable.

Anesthesia

No specific information is available. However, fasting should be avoided in HMG-CoA lyase deficiency, and a high carbohydrate intake must be ensured to minimize the risk of metabolic decompensations.