Propionic acidemia is a disorder of branch-chain amino acid and odd-chain fatty acid metabolism. The clinical features typically begin shortly after birth, with rare cases presenting in young adulthood. This disorder most commonly is characterized by episodic decompensations with dehydration, lethargy, nausea, and vomiting as well as a risk for neurologic sequelae. The defect is in the propionyl-CoA carboxylase enzyme with a resultant accumulation of toxic organic acid metabolites. Neuropathologic findings in this inborn error of metabolism have not been extensively characterized but include white matter spongiosis in neonates and a variable appearance in older children. We describe the pertinent literature on the neuropathology of propionic acidemia and a case report of a 4-year-old girl who had widespread gray matter vacuolization at postmortem examination. Although a previously unreported finding in propionic acidemia, diffuse gray matter vacuolization has been described in other fatty acid metabolic disorders.

Propionic acidemia, an inborn error of metabolism first described in 1961,1 was initially characterized in patients showing a markedly elevated serum glycine level. Elevated glycine is now known to occur in multiple enzyme deficiency disorders. Propionic acidemia was suspected of being a disorder of amino acid metabolism, and patients with this disorder had elevations of serum and urinary propionate. In 1969, a deficiency in the activity of propionyl-CoA carboxylase (PCC) in peripheral blood leukocytes was first demonstrated.2 

Propionic acidemia is an autosomal recessive inherited disorder with PCC mapped to chromosome 13q22-q34.3 PCC is a dodecamer with 6 β subunits and 6 biotin-containing α subunits.4 Defects have been shown to occur within both subunits.5 

Our case is of a 4-year-old girl diagnosed shortly after birth, who died from multiorganism bronchopneumonia after a protracted clinical course. Our postmortem neuropathology examination revealed widespread gray matter vacuolization, a finding not previously reported in this disorder.

Clinical Features

Propionic acidemia typically presents within the first few weeks of life, although rarely, a late onset in adulthood has been observed.6 The reason for this variance in onset is unknown. Common clinical features include poor feeding with vomiting, hypotonia, seizures, dehydration, and lethargy. Late manifestations result from progressive immune suppression with recurrent infections, bone marrow suppression, and neurologic sequelae.

The neurologic consequences of long-term survival include mental retardation, chorea, and pyramidal signs. Patients may have clinically disease-free periods between episodes of relapse that are triggered by high-protein intake, or they may have hypercatabolic states that are precipitated by fever or starvation. Chronic management is dependent on dietary control, carnitine supplementation, and alkaline therapy for chronic acidosis, with most patients failing to respond to biotin supplementation.6 

Clinical History

The patient was a 4-year-old girl born to a 16-year-old adolescent girl. The pregnancy was complicated by preeclampsia. She presented several days after birth with increasing lethargy, poor feeding, and hypothermia. Seizures were observed, and an electroencephalogram was abnormal. Laboratory tests showed the patient was acidotic with accompanying hyperammonemia (ammonia as NH3 >500 μg/dL [357 μmol/L]; normal range, 18–60 μg/dL [13–43 μmol/L]). A urine screen for organic acids showed increases in β-hydroxypropionate (4370 mmol/mol creatinine; normal range, 0–15), β-hydroxybutyrate (106 mmol/mol creatinine; normal range, 0–15), and methylcitrate (4648 mmol/mol creatinine; normal range, 0–20), all of which are consistent with propionic acidemia. Fibroblast cultures confirmed a specific deficiency of PCC (18 pmol/(min·mg) protein of methylmalonyl-CoA on low biotin culture medium; normal range, 128–537), with normal activity of pyruvate carboxylase and methylmalonyl-CoA carboxylase. Serum levels of propionate were also markedly elevated (up to 4400 μmol/L; normal range, 0–5 μmol/L).

The patient experienced multiple hospital admissions over her lifetime for vomiting, dehydration, and constipation with episodes of hyperammonemia in the 500-μg/dL range (357 μmol/L). Her serum propionate levels normalized to 16 μmol/L after dietary modifications that included Propimex formula and supplementation with carnitine and biotin, but these levels were frequently elevated on a subacute basis related to difficulties in maintaining adequate metabolic control. She continued to suffer from anemia (total hemoglobin level, 8.8 g/dL; normal range, 12–15.5 g/dL) and was treated with supplemental ferrous sulfate.

On her most recent admission, she presented with increasing lethargy and was unresponsive to sternal rubbing with fixed and dilated pupils (3–4 cm) on initial examination. She was intubated and resuscitated with intravenous fluids. Her admission laboratory examination revealed a serum bicarbonate level of 15 mEq/L (357 μmol/L) (normal range, 22–26 mEq/L [13–43 μmol/L]) and a serum ammonia level of 500 μg/dL (normal range, 18–60 μg/dL). Shortly after admission, she was febrile (39°C; normal range, 36.5°C–37.2°C) and in respiratory distress. She was started on intravenous cefotaxime. A chest x-ray film did not show infiltrates or increased haziness. A head computed tomographic examination was negative for intracranial hemorrhage and increased intracranial pressure. On transfer to the tertiary referral hospital for peritoneal dialysis, she was neutropenic (white blood cell count, 0.9 × 103/μL; normal range, 4.3–10.8 × 103/μL) and thrombocytopenic (platelet count, 0.9 × 103/μL; normal range, 150–300 × 103/μL). Blood cultures were drawn at the time of admission. She continued to be febrile and failed to regain consciousness. The patient's condition worsened, and she was transferred to intensive care, where she died the following day from presumed cardiopulmonary failure.

General Autopsy Findings

An autopsy was performed shortly after death and showed acute bronchopneumonia with Gomori methenamine silver–positive fungal organisms on lung sections supported by cultures positive for Candida sp. Examination of the bone marrow revealed a markedly hypoplastic marrow with less than 5% cellularity. In the sparse areas of cellularity, trilineage hematopoiesis was identified with normal maturation of hematopoietic precursors.

Neuropathology

A neuropathologic examination was performed as part of an unrestricted autopsy. The brain, dura, and spinal cord were removed and fixed for 2 weeks in 10% buffered formalin. The postfixation weight of the brain was 1005 g (mean for age, 1240 g). Gross examination revealed unremarkable dura, leptomeninges, and external vessels. The gyri and sulci were unremarkable. The cranial nerves were intact. The uncinate processes were symmetric. The brain stem and cerebellum were unremarkable. Sequential coronal sections of the cerebrum showed a well-defined gray-white matter junction. The cortex was not atrophic. The thalamus and other subcortical nuclei were grossly unremarkable. The ventricular system was symmetric but significantly dilated. At the level of the mammillary bodies, the lateral ventricle was markedly dilated, measuring 2.0 cm horizontally. The transverse diameter of the third ventricle measured 0.4 cm. The basis pedunculi were symmetric. The basis pontis was unremarkable. The medulla showed normal inferior olives and symmetric pyramids. Sagittal sections of the vermis and parasagittal sections of the cerebellum showed normal folia and white matter. The spinal cord and roots were unremarkable.

Histologic sections of the frontal and occipital cortices (the parietal cortex was not examined) showed a marked diffuse vacuolization around neurons and within the neuropil (Figure, A). The vacuoles were variable in size and distribution within the gray matter. White matter failed to show similar spongiotic changes. Occasional scattered neurons also showed eosinophilic cytoplasm indicative of acute hypoxic-ischemic injury. Metabolic glia were noted in the cortex and subcortical nuclei (Figure, B). Sections of the temporal cortex and hippocampus showed significant vacuolization of the background neuropil with occasional neuronal vacuolization. The temporal cortex also had scattered red neurons and mild, patchy neuronal dropout, especially within the Sommer sector (CA 1) of the hippocampus. Sections of the basal ganglia showed a similar pattern of vacuolization within the caudate, putamen, and globus pallidus but no evidence of hemorrhage.

A, Photomicrograph showing diffuse gray matter vacuolization within the occipital lobe (hematoxylin-eosin, original magnification ×40). Inset, high-power magnification of a neuron within the basal ganglia demonstrating vacuolization (hematoxylin-eosin, original magnification ×400). B, Glial cell from the dentate nucleus demonstrating pale-staining central chromatin with a prominent nuclear membrane, characteristic of an Alzheimer type II astrocyte (also called metabolic glia) (hematoxylin-eosin, original magnification ×400). C, Frontal cortex showing normal levels of myelination in the face of diffuse gray matter vacuolization (Luxol fast blue, original magnification ×40)

A, Photomicrograph showing diffuse gray matter vacuolization within the occipital lobe (hematoxylin-eosin, original magnification ×40). Inset, high-power magnification of a neuron within the basal ganglia demonstrating vacuolization (hematoxylin-eosin, original magnification ×400). B, Glial cell from the dentate nucleus demonstrating pale-staining central chromatin with a prominent nuclear membrane, characteristic of an Alzheimer type II astrocyte (also called metabolic glia) (hematoxylin-eosin, original magnification ×400). C, Frontal cortex showing normal levels of myelination in the face of diffuse gray matter vacuolization (Luxol fast blue, original magnification ×40)

Close modal

The cerebellar dentate nucleus showed prominent vacuolization and a moderate dropout of dentate neurons with an increase in reactive astrocytes and metabolic glia. The cerebellar cortex showed a patchy dropout of Purkinje cells and a proliferation of Bergmann glia. The olivary nucleus of the medulla showed a similar patchy dropout of neurons accompanied by an increase in reactive astrocytes. The basis pontis was unremarkable, but the tegmental white matter was somewhat vacuolated. Immunohistochemistry for the glial fibrillary acidic protein demonstrated a scattered increase in reactive astrocytes within the cerebellum and medulla. Spinal cord sections were unremarkable. Luxol fast blue, a myelin stain, showed a normal myelination pattern in the frontal cortex and pons (Figure, C).

PCC is a mitochondrial biotin-containing enzyme responsible for the conversion of propionyl-CoA to methylmalonyl-CoA. Propionyl accumulation results from defective branch-chain amino acid and odd-chain fatty acid metabolism. The resultant toxic build-up of organic acid metabolites, namely propionate, β-hydroxypropionate, β-hydroxybutyrate, and methylcitrate, is presumed to be responsible for the observed hyperammonemia, metabolic acidosis, and bone marrow suppression.7 The screening for this disorder is usually accomplished by urine organic acid analysis. Diagnosis is confirmed by demonstrating a deficiency of PCC in fibroblast culture.

In previous reports of the neuropathologic findings in this disorder, there has been a distinct histologic pattern present in neonates (Table). In neonates, spongiform degeneration of the white matter is seen, most prominently at the gray-white matter junction of the temporal cortex as well as at the white matter tracts in the midbrain, pons, and medulla.8,9 In older children, the histopathologic appearance becomes variable. Previous authors have recognized hypoxic changes with a dropout of Purkinje cells and granular layer neurons in the cerebellum and the presence of numerous Alzheimer type II astrocytes (metabolic glia) in the basal ganglia.10 Significant basal ganglia degeneration has also been reported in the case of a 16-year-old adolescent boy with marked associated movement disorder.11 There is one report of hemorrhage in the basal ganglia, speculated by the authors to be due to the increased sensitivity of these endothelial cells to toxic insults.12 

Neuropathologic Reports of Patients With Propionic Acidemia

Neuropathologic Reports of Patients With Propionic Acidemia
Neuropathologic Reports of Patients With Propionic Acidemia

Neuroradiologic examination of neonates reveals white matter attenuation on computed tomographic scanning and magnetic resonance imaging, mirroring the pathologic changes. After 1 year, these changes resolve on imaging, with only a minority of the patients developing symmetric basal ganglia changes.13 

The main histologic features of this case are extensive vacuolization; mild, hypoxic-ischemic injury; and proliferation of Alzheimer type II astroglia (metabolic glia). The differential degree of gray matter vacuolization between cortical areas, lack of white matter vacuolization, and noncorrespondence with hypoxic-ischemic areas argues against fixation artifact or brain ischemia as the primary cause of the vacuolization. Although there is a prior study of focal basal ganglia spongiform degeneration,8 such widespread cortical gray matter vacuolization has not been reported.

The etiology of white matter spongiform degeneration is still unclear. This change can be a nonspecific finding in fetal and neonate brains exposed to a wide variety of toxic insults. Anderson14 speculated that maternal detoxification in utero prevents a state of myelin poverty and that dietary corrections may be protective of white matter degeneration in older patients.

Gray matter vacuolization has been described in other disorders of fatty acid metabolism including long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.15 In this disorder of β-oxidation, the authors discovered widespread nonfatty deep gray matter vacuoles. They noted that toxic intermediates including acyl compounds enter the central nervous system.

These compounds may create selective pertubation in cell membrane permeability within the gray matter. Vacuolization in propionic acidemia may result from a similar process. It should be noted that our case was of an older child with a complex multiadmission clinical history and that there may be a temporal component to the development of these histologic changes.

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Author notes

Corresponding author: Brent T. Harris, MD, PhD, Department of Pathology HB 7600, Dartmouth Medical School, One Medical Center Dr, Lebanon, NH 03756 ([email protected])