An inborn error of metabolism presenting with apparently isolated subacute neuropsychiatric symptoms in an adolescent

Abstract

We discuss a previously healthy adolescent male presenting with subacute neuropsychiatric issues, tremors, hyperreflexia, and hypertension. Laboratory studies revealed acute on chronic kidney disease. Additional investigations yielded a treatable late-onset inborn error of metabolism (IEM). Late-onset forms of IEMs may present very differently than early-onset disease manifestations (e.g., neuropsychiatric issues may be the predominant symptom), thus leading to the underrecognition of a treatable underlying etiology.

Plain language summary

An inborn error of metabolism presenting with subacute neuropsychiatric symptoms

In this report, we discuss a previously healthy boy who developed mental health problems, shaking, and high blood pressure. Tests showed he had kidney issues, and further investigations revealed a treatable genetic metabolic disorder that appeared later in life. Unlike early forms of this disorder, this late-onset version can present with mainly neuropsychiatric problems. Physicians need to be vigilant to look for a treatable cause behind such symptoms.

A previously healthy 15-year-old male was transferred to our emergency room from an inpatient mental health facility, where he was admitted due to altered mood and behavior. Parents reported an approximate 3-month history of poor sleep with insomnia and excessive daytime sleepiness. Two weeks before the presentation, the patient developed “decreased activity” and “down mood,” auditory hallucinations of symphonies playing, and paucity of speech, ultimately leading to an admission to the inpatient psychiatry unit. He was transferred to our hospital for further evaluation of the above psychiatric issues, abnormal renal function, and hypertension.

Upon presentation, he had persistent systolic hypertension in the 130–150 range, diffuse tremulousness, hyperreflexia, and laboratory abnormalities notable for elevated creatine kinase of 301 U/L (reference: 30–200) and creatinine of 1.77 mg/dL (reference: 0.62–1.08). Complete blood count, inflammatory markers, urine drug screen, and urinalysis were unremarkable. Magnetic resonance imaging of the brain (with and without contrast) was unremarkable. During his initial interaction with the neurology team, he was awake and alert without aphasia, could follow simple commands and spell his name backward, could not do simple arithmetic, and required frequent stimulation to attend to the examiner. Pupils were equal and reactive to light. The muscle stretch reflexes were 4+ at bilateral quadriceps and 3+ at bilateral gastrocnemius with several beats of ankle clonus. Range of motion of neck and extremities, strength, and sensation were intact. Initial cerebrospinal fluid indices showed zero white and red blood cells, glucose 63 mg/dL (normal 60–80) and protein 18.4 mg/dL (normal 15–40). A routine elect0roencephalogram showed diffuse background slowing suggestive of generalized cerebral dysfunction. Laboratory tests for copper, zinc, vitamin B12, folate, thiamine, ammonia, homocysteine, and methylmalonic acid (MMA) levels were sent. The patient was started on lisinopril.

On day 8, the patient was transferred to the psychiatry unit for symptomatic management. On hospital day 10, MMA and homocysteine test results revealed significant elevations at 109,900 nmol/L (reference range: 87–318) and 183 μmol/L (reference range: <11.4) respectively, with normal B12 and folate. Ammonia, zinc, copper, and thiamine also resulted within normal limits. Upon receipt of elevated MMA and homocysteine, he was transferred from inpatient psychiatry to pediatrics for close monitoring for complications of hyperhomocysteinemia. Genetics/metabolic experts were consulted. Expanded metabolic testing with plasma amino and urine organic acids, plasma acylcarnitine profile, free and total carnitine as well as targeted genetic testing (MMA and homocystinuria genetic panel) were sent. The patient was started on empiric treatment for presumed cobalamin C (cblC) deficiency with hydroxocobalamin (OHCbl), folinic acid, and betaine on hospital day 11. The patient experienced a first-time generalized tonic-clonic seizure on hospital day 16 despite treatment with OHCbl and was started on levetiracetam for further seizure prevention.

Plasma amino acid testing was notable for elevated homocysteine level at 33 μmol/L (reference: 0), low-normal methionine at 11 μmol/L (reference range: 10–32), and several additional mild, nonspecific amino acid elevations. Urine organic acid testing revealed significantly elevated MMA concentration of 636 mmole/mole creatinine (reference range: 1–4). The plasma acylcarnitine profile showed elevated propionyl (C3) and methylmalonyl-/succinyl (C4-DC) acylcarnitine species of 8.45 μm (reference range: 0–1.56) and 4.43 μm (reference range: 0–0.22), respectively. These results were consistent with an inherited disorder of cobalamin metabolism. Genetic testing showed biallelic pathogenic MMACHC variants in trans. The patient’s variants are c.482G>A (p.Arg161Gln) and c.599G>A (p.Trp200*), both classified as pathogenic; therefore, the cause of his elevated homocysteine and MMA. He was ultimately transferred back to inpatient psychiatry for ongoing medication adjustments and discharged on hospital day 37 on olanzapine, melatonin, levetiracetam, OHCbl, leucovorin, levocarnitine, and betaine. He continued to follow with genetics and psychiatry outpatient and was successfully weaned off psychotropic medications and levetiracetam without seizure recurrence.

Discussion

cblC deficiency, also known as methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of vitamin B12 (cobalamin) metabolism. It is an autosomal recessive disease caused by biallelic pathogenic variants in the MMACHC gene, which encodes a chaperone protein involved in the intracellular trafficking and transformation of cobalamin to methylcobalamin and adenosylcobalamin. The former is a coenzyme for methionine synthase, which converts homocysteine to methionine. The latter is a coenzyme for methylmalonyl-CoA mutase, which converts l-methylmalonyl-CoA to succinyl-CoA1. As a result, cblC deficiency leads to combined methylmalonic aciduria, homocystinuria, and low methionine (biochemical hallmarks of the disease). CblC is a multisystemic disease with a broad array of manifestations that may range from in utero to adult-onset forms. It commonly affects the neurological and hematological systems.^1,2

Though included in the Alabama state newborn screen, patients with the milder forms of disease may have mild enough metabolic abnormalities at birth to be missed by newborn screening. Early-onset forms usually present with poor growth, developmental delay, hypotonia, microcephaly, seizures, cytopenia, and hemolytic uremic syndrome. On the other hand, the adult-onset forms frequently present with neuropsychiatric symptoms, thromboembolic events or seizures secondary to hyperhomocysteinemia, and subacute combined degeneration of the spine. The neuropsychiatric presentation may include behavioral changes, hallucinations, psychosis, cognitive decline, and/or dementia. ² This constellation of symptoms is well known to clinicians in association with the nutritional deficiency of vitamin B12. However, in cblC, the serum vitamin B12 level is irrelevant and may be normal, low, or high, which may detract the clinicians from the possibility of disorders of intracellular cobalamin metabolism. The functional deficiency of B12 can be indirectly assessed by measuring plasma homocysteine (Hcy) and MMA levels. ² The low levels of methionine on detailed plasma amino acid analysis may also suggest CblC and other re-methylation defects. Confirmation of cblC requires genetic testing that reveals biallelic variants in the MMACHC gene. The mainstay of therapy is focused on lowering MMA and Hcy levels via parenteral OHCbl and betaine.^1,2 Betaine serves as a provider of methyl groups in the process of converting Hcy to methionine through betaine-homocysteine methyltransferase, thereby circumventing the methylcobalamin-dependent pathway. ²

In patients with late-onset inborn error of metabolisms (IEMs), the variability of the signs and symptoms may be confusing. An absence of family history, varying timelines for psychiatric and somatic symptoms, and undiscovered clinical signs (e.g., difficult-to-detect peripheral neuropathies, cataracts, and organ dysfunction) may make it challenging to decide which patients may have an underlying IEM and should undergo specific investigations versus those with an initial presentation of a primary psychiatric condition. Nevertheless, late-onset IEMs should be considered in older patients with acute and recurrent attacks of confusion or behavioral change with physical signs (gastrointestinal, dysautonomia, alteration of awareness, pyramidal signs, etc.) or isolated psychiatric signs in previously asymptomatic adolescents or adults, fluctuating symptoms with resistance or, in some cases, deterioration with typical psychiatric treatment, and cognitive decline.^3,4

In summary, while clearly recognized syndromes may be identifiable to the trained eye, the rare, late-onset IEMs require a high index of suspicion by front-line healthcare providers due to the nonspecific nature of their presenting symptoms.