Movement Disorder Following Hypoglycemic Encephalopathy in Mitochondrial 3-Hydroxy-3-methylglutaryl-CoA Synthase-2 (mHS) Deficiency

Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHS) deficiency is an ultra-rare inborn error of ketone body synthesis that is caused by biallelic mutations in HMGCS2. The manifestations of mHS deficiency can include hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, hyperammonemia, and hepatomegaly. Here, we report a case of movement disorder following hypoglycemic encephalopathy involving the basal ganglia in a patient with mHS deficiency. Exome sequencing showed novel compound heterozygous variants in HMGCS2, a partial gene deletion (classified as pathogenic) and c.704T>A (p.M235K) variant that was deemed to be likely pathogenic. Our findings suggest that mHS deficiency can result in basal ganglia injury and movement disorder.

Background

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHS) deficiency is an ultra-rare inborn error of ketone body synthesis that is caused by biallelic (homozygous or compound heterozygous) mutations in HMGCS2 (1, 2). With only very few (<30) cases reported in the clinical scientific literature (1, 3), the birth prevalence and spectrum of clinical manifestations of mHS deficiency are subjects of ongoing studies. HMG-CoA synthase plays a key role in the formation of HMG-CoA, a critical intermediate for ketogenesis and cholesterol biosynthesis. HMGCS2 encodes the mitochondrial isoform of HMG-CoA synthase, whereas HMGCS1 encodes the cytoplasmic isoform (1, 2). Patients with mHS deficiency tend to present around infancy, following a period of prolonged fasting or intercurrent illness (2, 3). The clinical manifestations of mHS deficiency can include a variable combination of hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, white matter hyperintensities, hyperammonemia, hepatomegaly, dyslipidemia, and coagulopathy (1–3). Although white matter abnormalities (2) and coagulopathy (1) have been reported in patients with mHS deficiency, movement disorders have not previously been described in mHS deficiency to our knowledge. Here, we report a case of involuntary choreiform movements and dystonia in a patient with mHS who sustained basal ganglia injury following an episode of severe hypoglycemia in infancy.

Case Report

Our index case is a 25-year-old man who presented to the genomics clinic with ongoing concerns of involuntary choreiform movements and dystonia. The choreiform movements and dystonia reportedly began after a severe hypoglycemic episode in infancy. His parents were subsequently advised to ensure strict avoidance of fasting. He was never able to walk independently following the stroke episode. Aside from the motor delays, he attained the remainder of his developmental milestones (including cognitive, social, and speech) at an appropriate age. There have been no concerns regarding his intellectual abilities. The remainder of his medical history was essentially noncontributory.

Given the persistence of the involuntary choreiform movements and dystonia, he had extensive assessments and investigations for movement disorders. These assessments and investigations were all nondiagnostic, which prompted referral to clinical genomics specialists. On physical examination in the genomics clinic, there were no apparent dysmorphisms, malformations, or anomalies. The patient subsequently had magnetic resonance imaging of the brain, which showed symmetrical volume loss of the basal ganglia, particularly the caudate heads, as well as symmetrical subtle T2 fluid-attenuated inversion recovery signal abnormality of the posterior limbs of both internal capsules extending along the corticospinal tract bilaterally (Figure 1). The magnetic resonance imaging findings are compatible with chronic findings of encephalomalacia and gliosis, likely related to distant insult. The symmetrical distribution of the findings suggests a toxic or metabolic cause and the location of findings within the basal ganglia and posterior limb of the internal capsule have been associated with hypoglycemic encephalopathy. These findings suggest that inborn errors of metabolism can result in an increased risk for severe hypoglycemic injury. The patient had trio (proband and parents) exome sequencing with mitochondrial genome sequencing at the GeneDx laboratory (Gaithersburg, MD, USA). Exome sequencing showed a maternally inherited deletion (chr1:120 294 873–120 307 415 del; hg19) resulting in the deletion of HMGCS2 exons 2–8 (classified as pathogenic) [NM_0 05518.3] and a paternally inherited missense variant c.704T>A, p.M235K (classified as likely pathogenic) in HMGCS2 [NM_0 05518.3], which suggested a diagnosis of autosomal-recessive mHS deficiency. To our knowledge, neither variant has been reported previously. Deletion of exons 2–8 (about 12.5 kb) of HMGCS2 fulfilled PVS1, PM2, and PP4 criteria of the ACMG variant classification system (4). HMGCS2 c.704T>A, p.M235K fulfilled PM3, PM2, PP2, and PP3 criteria of the ACMG variant classification system.

Figure 1.

Axial (A) and coronal (B) T2 FLAIR MRI of the brain demonstrates symmetric volume loss of the basal ganglia, particularly marked in both caudate heads (blue arrows). Thin curvilinear FLAIR hyperintensity within both caudate heads and putamen (blue arrowheads) likely reflects gliosis. There is also subtle FLAIR hyperintensity along the posterior limb of both internal capsules, with extension along the corticospinal tract bilaterally (white arrowheads). These findings likely reflect chronic sequelae of an old injury. The symmetricity of the findings suggests a toxic or metabolic cause. The basal ganglia and posterior limb of the internal capsule are characteristic areas of MRI signal abnormality in severe hypoglycemia. FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.

Discussion

Here, we report, to our knowledge, the first case of hypoglycemia-associated stroke and movement disorder in mHS deficiency, an ultra-rare hereditary metabolic disorder. Although some inborn errors of metabolism are known to be associated with an increased risk for stroke (5), to our knowledge, this is the first report of stroke and movement disorder in a patient with mHS deficiency. In addition, we report two novel variants in HMGCS2 that are associated with mHS deficiency. Our findings expand both the genotype and phenotype spectrum of mHS deficiency, an ultra-rare (with extremely few cases reported hitherto) inherited metabolic disorder (2, 3, 6).

The mechanism(s) underpinning the stroke episode and movement disorder observed in mHS deficiency in this study are still unclear. It is possible that the patient sustained a metabolic and/or ischemic stroke. Some Mendelian disorders that are also associated with metabolic dysfunction, including an increased risk for severe hypoglycemia, can manifest with metabolic stroke (or stroke-like) episodes without apparent findings of vessel occlusion or rupture or the confirmation of ischemia in the typical vascular territories (5). Exposure to hypoglycemia has been associated with a potentially increased risk for coagulopathy and stroke based on studies of glycemic control in patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) (7–9). Several lines of evidence suggest that recurrent exposure to hypoglycemia may increase the risk for coagulopathy and stroke regardless of whether the patient had DM (10, 11). A recent report by El-Sayed and colleagues showed that coagulopathy can occur during hypoglycemic episodes in mHS deficiency (1), consistent with findings from some previous studies on the risk for coagulopathy in hypoglycemic patients (8). Multifocal hyperintensities involving different brain areas, including the basal ganglia, have been reported in mHS deficiency (2).

Hypoglycemia is a common clinical finding that can arise from diverse causes (8, 12). An improved awareness of the potential risk for stroke (metabolic and/or ischemic) in patients with severe hypoglycemia may reduce morbidity and mortality (13). Episodes of hypoglycemia impact on brain nutrient metabolism (14) and function (12). Recent studies have shown that acute severe episodes of hypoglycemia may alter the brain microvascular proteome in mice and potentially impact on cerebrovascular function (15). A better understanding of molecular mechanisms underpinning hypoglycemic encephalopathy may pave the way for preventive strategies (8, 9). Our findings not only complement the previous reports of hypoglycemic encephalopathy in T1DM as well as T2DM (8) but we also provide supportive evidence based on ultra-rare HMGCS2-related mHS deficiency. Overall, our findings underscore the critical need for health care providers to consider the potential risk(s) of brain injury in patients with hypoglycemia-prone disorders, including HMGCS2-related mHS deficiency.