41.1 Clinical Features
and Laboratory Investigations 3-Hydroxy-3-methylglutaryl-coenzyme A lyase (HMG- CoA lyase) deficiency is a rare inborn error of metab- olism with an autosomal recessive mode of inheri- tance. About 50% of the patients present in the neonatal period after a brief symptom-free period.
Most of the rest become symptomatic before the age of 1 year. Presentation after the age of 2 years is rare.
Episodes of deterioration are provoked by fasting, in- fections, and high protein intake. The episodes are characterized by lowering of consciousness, hypoto- nia, sometimes seizures, and apnea. Many patients have hepatomegaly. Some patients die from deep hy- poglycemia. With appropriate treatment, most pa- tients recover from their initial episode of metabolic decompensation, but there may be remaining neuro- logical sequelae, including microcephaly, mental re- tardation, visual impairment, epilepsy, and central motor deficits.
Laboratory examinations during these episodes always reveal an acidosis and almost always hypo- glycemia, which is often profound. Ketone bodies are inappropriately low. Lactate may be markedly elevat- ed, especially in neonates. Many patients have abnor- mal liver function tests and hyperammonemia. Pan- creatitis is another complication that may occur. Uri- nary organic acid analysis reveals increased excretion of 3-hydroxy-3-methylglutaric acid, 3-hydroxyisova- leric acid, 3-methylglutaconic acid, and 3-methylglu- taric acid. 3-Methylcrotonylglycine may also be pre- sent. The diagnosis is confirmed by enzyme assess- ment in leukocytes or cultured fibroblasts. Fasting and leucine loading are usually unnecessary for diag- nosis. They may be useful to determine fasting and protein tolerance, but they carry the risk of invoking metabolic decompensation and should be performed under close supervision. DNA confirmation is op- tional. Neonatal screening is possible using analysis of 3-methylglutarylcarnitine in blood. Prenatal diag- nosis can be performed using metabolite measure- ments, enzyme essays, and molecular techniques.
41.2 Pathology
Zoghbi et al. (1986) reported the findings of a brain biopsy during an episode of metabolic decompensa- tion. No abnormalities were found in the cerebral cor- tex. In the white matter spongiosis, reactive gliosis, and increased intracellular astrocytic glycogen were found. Gibson et al. (1994) reported spongiform de- generative changes and generalized edema in a child who died during a metabolic crisis. The histopatho- logical basis of the focal and diffuse white matter sig- nal abnormalities in well-treated and clinically nor- mal patients is unknown.
41.3 Pathogenetic Considerations
HMG-CoA lyase is a key enzyme in leucine degrada- tion and in ketogenesis. The gene encoding HMG- CoA lyase, HMGCL, is located on chromosome 1p35.1–36.1. The enzyme HMG-CoA lyase is located in mitochondria and peroxisomes of all tissues.
Leucine is sequentially converted to 3-methyl- crotonyl-CoA, 3-methylglutaconyl-CoA, and HMG- CoA. Fatty acid degradation leads to the formation of acetyl-CoA, which joins acetoacetyl-CoA to form HMG-CoA. HMG-CoA lyase catalyzes the conversion of HMG-CoA to acetoacetate. Acetoacetate and 3-hydroxybutyrate are the principal ketone bodies.
3-Hydroxybutyrate is derived directly from acetoac- etate in a dehydrogenase reaction. A third ketone body, acetone, arises from decarboxylation of ace- toacetate. Ketone bodies are formed predominantly from fatty acids and ketogenic amino acids, princi- pally leucine. Ketone bodies are used as alternative source of energy for the brain when production of energy from glucose is insufficient to meet the de- mands. The main function of ketone bodies may be to provide the brain with a noncarbohydrate energy source during fasting. The brain cannot use fatty acids as an energy source. Under normal conditions, the main energy substrates of the brain are glucose and its derivatives, such as lactate, but during pro- longed fasting ketone bodies supply almost two- thirds of the brain energy. Ketone bodies have a glu- cose sparing effect, turning down peripheral and cen- tral glucose utilization. They also reduce muscular proteolysis.
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
In HMG-CoA lyase deficiency multiple different mutations have been identified in HMGCL but so far no clear genotype–phenotype correlation has been found. HMG-CoA lyase deficiency causes a block in the production of ketone bodies, leading to exhaus- tion of glucose to very low levels under conditions when ketogenesis is required, that is, insufficient availability of glucose to meet energy demands. The metabolic decompensation is characterized by hy- poketotic hypoglycemia. Infancy is the period of highest risk for decompensation.
In patients who survived a period of profound hy- poglycemia in the neonatal period the remaining cerebral damage may mainly involve the posterior part of the brain, as typically happens in neonatal hy- poglycemia. The cause of the remaining white matter abnormalities seen in patients with HMG-CoA lyase deficiency is unknown. These abnormalities must somehow be related to the specific metabolic de- rangement, because they are not seen in other disor- ders with hypoketotic hypoglycemia.
41.4 Therapy
The mainstay of treatment is suppression of ketogen- esis. During a metabolic crisis, immediate attention should be focused on correction of the blood pH by sodium bicarbonate infusions and elevation of blood glucose by glucose infusions. In addition, patients may require measures of general support including assisted ventilation and repair of electrolyte and fluid deficits.
Long-term management of HMG-CoA-lyase-defi- cient patients should focus on avoidance of hypo- glycemia and of long fasts. A high-carbohydrate diet is recommended with moderate protein and fat re- striction. The leucine intake should be adjusted to in- sure normal growth. Patients should be under con- stant observation during periods of intercurrent ill- ness. A high carbohydrate intake must be maintained during any metabolic stress. If high carbohydrate in- take cannot be maintained, patients should be admit- ted for intravenous glucose administration.
Once the diagnosis has been established and this treatment strategy is applied, further neurological damage is usually prevented.
41.5 Magnetic Resonance Imaging
CT scan findings during a metabolic crisis in the neonatal period are characterized by white matter hypodensity and swelling. In the occipital region, contrast between the cortex and white matter may have disappeared and follow-up CT may show severe cystic degeneration of the occipital and parieto-oc- cipital white matter. These findings are not specific for HMG-CoA lyase deficiency, but are characteristic sequelae of profound neonatal hypoglycemia. Follow- up MRI shows evidence of gliotic scarring and atro- phy of the area involved (Fig. 41.1). In addition, le- sions in the globus pallidus, thalamus, putamen, and caudate nucleus may occur following a neonatal hypoglycemic crisis (Fig. 41.1).
Hypoglycemia after the neonatal period usually leads to more diffuse cerebral cortical damage. In some children a stroke, e.g., a unilateral anterior and middle cerebral artery infarction arising during a metabolic crisis, has been reported. In an untreated infant with a moderately severe chronic metabolic de- rangement, macrocephaly and diffuse white matter hypodensity and swelling have been reported (Lisson et al. 1981; Leupold et al. 1982), suggesting diffuse white matter spongiosis. Cystic degeneration of the white matter was documented on follow-up.
MRI findings that are characteristic of HMG-CoA lyase deficiency include multiple abnormal white matter foci, varying in number from a few to, more often, a multitude and varying in size from very small – a few millimeters – to larger and more confluent le- sions (Figs. 41.2 and 41.3). The abnormal white mat- ter foci may be seen on a background of slight to mild signal abnormalities of almost the entire cerebral white matter, sparing the corpus callosum, variably sparing the U fibers (Fig. 41.2). The combination of diffuse mild and multifocal more serious cerebral white matter abnormalities is unique. In addition, sig- nal abnormalities may be seen in the posterior limb of the internal capsule, hilus of the dentate nucleus, the dentate nucleus, and pontine tegmentum (Figs. 41.1–
41.3). The cerebellar white matter is spared. These ab- normalities are also seen in well-treated patients who have never experienced a metabolic crisis and who are clinically normal. The striking discrepancy be- tween the serious white matter abnormalities on MRI and the lack of clinical findings in these patients is unexplained. This observation excludes demyelina- tion as histopathological basis.
Chapter 41 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency 322
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Fig. 41.1. This 4-year-old girl with HMG-CoA lyase deficiency experienced serious hypoglycemia in the neonatal period. She is severely retarded and has a visual impairment and micro- cephaly. MRI shows damage of the parieto-occipital white and gray matter, as may occur after neonatal hypoglycemia. In
addition, mild signal changes are present in the basal ganglia, thalami, and dentate nuclei. The cerebral white matter is dif- fusely abnormal. The corpus callosum is spared. From van der Knaap et al. (1998), with permission
Chapter 41 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency 324
Fig. 41.2. The 10-year-old sister of the patient in Fig. 41.1 also has HMG-CoA lyase deficiency, but never developed symp- toms of the disease. She was diagnosed after the diagnosis was established in her sister. The T2-weighted images show diffuse mild signal changes in the cerebral white matter with additional spots of more prominent signal abnormality. The
T1-weighted images only show the areas of more prominent signal abnormality; the diffuse signal changes are difficult to see. The corpus callosum is not involved. Signal abnormalities are also seen in the dentate nucleus and the hilus of the den- tate nucleus. From van der Knaap et al. (1998), with permission 041_Valk_3_Hydroxy 08.04.2005 15:58 Uhr Seite 324
Fig. 41.3. A 6-year-old boy with HMG-CoA lyase deficiency. He had two episodes of hypoglycemia and lethargy in his third year of life, but his condition was never serious. His intelligence and neurological examination are normal. MRI reveals diffuse signal changes in the cerebral white matter, sparing the U fibers, with multiple foci of more prominent signal abnormali-
ty. These spots are also seen on the IR images (upper row, left).
Slight signal changes are seen in the posterior limb of the in- ternal capsule, thalami, pontine tegmentum, dentate nucleus, and outflow tract of the dentate nucleus. From van der Knaap et al. (1998), with permission
