Late onset AMACR deficiency with metabolic stroke-like episodes and seizures

Abstract

Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal disorder causing pristanic acid accumulation. Only 16 cases have been described so far. A female in her seventh decade presented with episodes of dysphasia, headache and sensory disturbance inconsistent with migraine, epilepsy or transient ischaemic attack. An MRI demonstrated unusual changes in the pons, red nuclei, thalami and white matter. Mitochondrial disease was suspected but detailed testing was negative. After eight years of symptoms, she developed a febrile encephalopathy with hemispheric dysfunction, focal convulsive seizures and coma. Her condition stabilised after one month. Lacosamide was continued for seizure prevention. The diagnosis remained elusive until whole genome sequencing revealed AMACR deficiency. Pristanic acid levels were highly elevated and dietary modification was recommended. Genetic peroxisomal disorders can present in older age; our patient is the oldest in the AMACR deficiency literature. Novel features in our case include central apnoea, dystonia and rapid eye movement behaviour disorder.

Background

A patient with a mitochondrial-like encephalopathic illness was diagnosed with alpha-methylacyl-CoA racemase (AMACR) deficiency after whole genome sequencing. It is a rare peroxisomal disorder leading to the accumulation of pristanic acid. Only 16 cases are described in 12 adults and four infants (table 1). Our case has the oldest onset. We provide a longitudinal summary of clinical and imaging findings, and report novel findings of toe dystonia, rapid eye movement (REM) behavioural disorder and central apnoea.

Table 1.

Summary of known adult and paediatric cases with AMACR deficiency

Author	Sex, decade onset (diagnosis)	Gene variant*	Pristanic acid†	Clinical features	Encephalopathic illness	MRI and biopsy findings	Outcome
Ferdinandusse et al16	F, fifth (fifth)	c.154T>C	109	Demyelinating neuropathy, spastic paraparesis, migraine and hypothyroid	–	Normal MRI of cervical spine	–
McLean et al11	M, second (fifth)	c.154T>C	105	RP, optic atrophy, cataracts, axonal neuropathy, recurrent seizures, SE, LD, hypogonadism and micrognathia	1x	Minor cerebral atrophy and normal white matter	Progressive sight loss. Slow recovery
Clarke et al9	F, fifth (sixth)	c.154T>C	316	Cataracts, RP, optic atrophy, tremor, migraine, depression and asthma	1× with seizures	Hyperintensity of pons, basal ganglia, thalami and cerebral peduncles	Deterioration with elevated pristanic acid levels despite PLEX
Thompson et al6	F, second (sixth)	c.154T>C	348	Axonal neuropathy, recurrent seizures, cognitive decline, gait apraxia and depression	5×	Cortex, subcortical white matter, pontine and thalamic hyperintensity	–
Smith et al13	M, second (fifth)	c.154T>C	42	RP, neuropathy, recurrent seizures, LD and hypogonadism	2× 1 with NCSE	Unilateral cortical hyperintensity. Biopsy with chronic necrotising encephalitis	Remission at 16 months with diet restriction
Kapina et al17	M, third (fourth)	c.559G>A	130	Retinopathy, axonal neuropathy, schizophrenia and recurrent rhabdomyolysis	2× with seizures	Hyperintensity of thalami, pons and cerebral peduncles. Acute oedema. Biopsy shows ischaemia	Partial recovery. Reduced pristanic levels with diet restriction
Dick et al18	M, sixth (sixth)	c.154T>C	76	Neuropathy, recurrent seizures, ataxia and cognitive decline	–	White matter, thalamic, midbrain and pontine hyperintensity. Brainstem and frontal atrophy	–
Stewart et al12	M, third (fifth)	–	30	RPA, recurrent seizures and low testosterone	1× with seizures	Thalamic, left hemisphere, pontine and midbrain hyperintensity. Biopsy shows chronic inflammation	Seizure free at 12 months with diet restriction
Haugarvoll et al7	M, fourth (fifth)	c.367G>A	–	Cataracts, RPA, symptomatic demyelinating neuropathy, diabetes and steatohepatitis	1×	Pontine, midbrain and thalamic hyperintensity	Deceased, liver sarcoma
Haugarvoll et al7	F, fourth (fifth)	c.367G>A	169	RPA, cataracts, neuropathy, recurrent seizures, tremor, diabetes and transient deficits	1×	Pontine, midbrain and thalamic hyperintensity	Started on diet
Krett et al15	M, second (sixth)	c.154T>C	–	Subclinical seizures, depression, bipolar, gynaecomastia, high arch palate and recurrent rhabdomyolysis	1×	–	Started on diet. Deceased after femoral fracture
Index case	F, seventh (eighth)	c.154T>C	117	Transient deficits, tremor, toe dystonia, cataracts, hypothyroidism, glaucoma, central apnoea and REMBD	1× with seizures	White matter, thalamic and pontine hyperintensity. Acute swelling and hemispheric signal change	Seizure/acute deficit free after 4 years. Lacosamide and 1-year diet
Van Veldhoven et al19	F, first (first)	–	–	Vitamin K deficiency and giant cell neonatal hepatitis	–	–	–
Setchell et al20	F, first (first)	c.154T>C	4.4 (µg/mL)	Vitamin K deficiency and deranged liver function tests	–	Mild under-myelination on MRI	Stable on cholic acid and vitamin supplements
Verhagen et al21	M, first (first)	deletion 5p13.3	93	Incidental AMACR deficiency while investigating oculocutaneous albinism	–	–	–
Gündüz et al22	M, first (first)	c.596G>A	28	Elevated liver enzymes	–	Normal	Normal at 7.5 years. Mildly elevated liver enzymes

*All are homozygous pathogenic variants.

†Units expressed as µmol/L unless otherwise stated. Normal pristanic acid level <3 µmol/L.

AMACR, alpha-methylacyl-CoA racemase; LD, learning disabilities; NCSE, non-convulsive status epilepticus; PLEX, plasma exchange; REMBD, rapid eye movement behavioural disorder; RP, retinitis pigmentosa; RPA, retinal pigmentary atrophy; SE, status epilepticus.

Case presentation

A female in the seventh decade presented with atypical stroke-like episodes of expressive dysphasia, dysarthria, headache and right-hand sensory disturbance. There were six episodes in six months, evolving over 10 min, and resolving after three hours. Her background included chronic obstructive pulmonary disease, hypertension, psoriasis, anxiety and depression for which she took citalopram. She smoked seven cigarettes daily and occasionally drank alcohol. There was no relevant family history and no consanguinity. On examination, the only finding was a mild postural tremor, present for 10 years. MRI revealed bilateral symmetric T2 high signal change of the superior cerebellar peduncles, pons, midbrain (tegmentum and tectum), subthalamic nuclei, thalami and connecting fibres (figure 1A and B). The pyramidal tracts were spared. There were also periventricular and subcortical white matter hyperintensities particularly at the frontal lobes and the external capsules (figure 1A and B). These appearances were not in keeping with microvascular disease and seemed to involve the cerebellar afferent and efferent pathways (cerebellothalamic tract). There was volume loss in the parietal lobes. There was no evidence of acute or prior infarct. Despite the atypical features, she was covered for transient ischaemic attacks with an antiplatelet and statin.

Figure 1.

Initial coronal (A) and axial T2 fluid-attenuated inversion recovery (FLAIR) (B) demonstrating generalised prominence of cerebrospinal fluid spaces and high signal involving the pons, midbrain tegmentum, thalami and connecting fibres (red arrows) in addition to periventricular white matter (blue arrows). (C) Axial T2 FLAIR demonstrating prominent new right hemispheric cortical and juxtacortical signal abnormality (yellow arrows) eight years after initial presentation and two months after encephalopathic illness. (D) Resolution of the cortical T2 signal abnormality but subtle focal right hemispheric volume loss on follow-up imaging 10 months after encephalopathic illness.

She continued with infrequent episodes of transient neurological disturbance despite warfarin for subsequent atrial fibrillation and pizotifen for possible migraine. Some episodes were associated with confusion, but no convulsive seizure activity was witnessed. Her mobility and coordination slowly deteriorated but not in a stepwise fashion and eventually she needed assistance with activities of daily living. The tremor gradually worsened and an intention component developed. There was no response to propranolol or pramipexole. She also developed restricted up gaze, intermittent toe dystonia and symptoms of REM behavioural disorder. Five sequential MRIs over eight years showed stable appearances apart from subtle widespread volume loss. Vessel imaging was normal. There was never any evidence of acute ischaemia on diffusion weighted imaging to suggest cerebrovascular disease, or cerebral microbleeds on T2* that might have suggested cerebral amyloid angiopathy and amyloid spells. An electroencephalograph (EEG) was normal. A muscle biopsy and full mitochondrial genome analysis was normal. She had a normal dopamine transporter scan. Due to the gait disorder and intention tremor, genetic testing for spinocerebellar ataxias was performed (SCA 1, 2, 3, 6, 7 and 17) but was normal.

Eight years after her initial presentation she developed a febrile encephalopathy with impaired consciousness and left-sided focal convulsive seizures, haemianopia, sensory inattention and weakness. This followed a day of vomiting and reduced oral intake. An MRI on admission was stable with no acute changes. Despite supportive treatment and levetiracetam, she required sedation, intubation and ventilation for seizure control. Phenobarbitone, propofol, clonazepam and lacosamide were added. She had normal interictal EEG recordings. One EEG after a focal convulsive seizure demonstrated postictal slowing. Eventually, the focal seizures settled but she remained encephalopathic. There was no evidence of non-convulsive status. Her seizures seemed to settle with the addition of lacosamide so it was continued as monotherapy and the other agents withdrawn. The encephalopathy lasted four weeks before improving and after two months of rehabilitation she recovered to her functional baseline. A repeat MRI two months into the admission demonstrated cortical signal change and swelling of the right cerebral hemisphere (figure 1C). An MRI spectroscopy revealed normal spectrum and an absent lactate peak; there were no features of necrosis, infection or mitochondrial disease. At 10 months, the cortical signal change improved leaving right hemisphere volume loss (figure 1D). She was enrolled in the 100 000 genome project. Two years later, this revealed a homozygous pathogenic variant of the AMACR gene (c.154T>C, p.(Ser52Pro)). She had significantly elevated serum pristanic acid (117.46 μmol/L, normal: <3 μmol/L). Phytanic acid and very long chain fatty acids (VLCFA) were normal as expected.

Outcome and follow-up

Our patient is free from seizures and transient neurological events with four years of lacosamide and one year of low pristanic and phytanic acid diet. She subsequently developed respiration pauses. On examination 12 years after initial presentation, there is mild limb ataxia, prominent intention tremor, restricted up gaze, normal funduscopy, visual loss due to glaucoma and cataracts, and reduced reflexes but no other suggestion of neuropathy. She mobilises with a stick but needs a wheelchair for long distances.

Discussion

Peroxisomal disorders

All eukaryotic cells have peroxisomes. They synthesise etherphospholipids and oxidise fatty acids.¹ When peroxisomal function is lost, patients accumulate VLCFA, branched chain fatty acids (pristanic acid and phytanic acid) and the bile acid intermediates di-hydroxycholestanoic (DHCA) and tri-hydroxycholestanoic acid (THCA) leading to peroxisomal biogenesis disorders like Zellweger syndrome.¹ The AMACR enzyme is essential for stereo-isomerisation. Patients with AMACR deficiency accumulate incorrect isomers of pristanic acid, DHCA and THCA, but the correct isomers are oxidised.¹ Breast milk, krill, fish and bovine fat are human dietary sources of pristanic acid. In addition, phytanic acid from dairy or ruminant fats can be oxidised to pristanic acid.² Pristanic and phytanic acid are cytotoxic in excess. They induce nitric oxide-dependent apoptosis in vascular smooth muscle cells.³ In rat hippocampi, cell death has been demonstrated in addition to calcium influx (particularly with oligodendrocytes), mitochondrial membrane disruption and generation of reactive oxygen species.⁴ Adult onset Refsums disease (ARD) leads to phytanic acid accumulation and has similarities with AMACR deficiency; both predispose to retinitis pigmentosa, neuropathies and ataxia.⁵ ARD differs by also causing cardiac arrythmias and shortened metacarpals/metatarsals.⁵ MRI changes are not seen in ARD, but they are seen in AMACR deficiency and can be seen in other peroxisomal disorders.⁵

AMACR deficiency cases

There are 12 adult and four infant reports of AMACR deficiency (table 1). It is an autosomal recessive condition, consanguinity reported in five. Cases with symptomatic infantile onset have abnormal liver enzymes, vitamin K deficiency or hepatitis. They have a different phenotype to adult cases and are considered separately. In adult cases, a homozygous (c.154T>C, p.(Ser52Pro)) pathogenic variant of the AMACR gene is commonly seen (75%). Pristanic acid levels were elevated in all cases. Bile acid intermediates were elevated in six of the seven tested. There is no gender predominance (58% male). Symptom onset varied from second to seventh decades of life (average third). Delay in onset may be due to accumulated metabolic injury.

Ten adult patients (83%) developed an encephalopathic illness resembling mitochondrial stroke-like episodes with hemispheric symptoms, seizures, coma and fever (table 1). Only three (25%) had recurrent episodes. Encephalopathic illnesses were sometimes preceded by reduced oral intake and vomiting. Other triggers include pregnancy and weight loss.^{6 7} This is similar to ARD exacerbations where periods of fasting lead to phytanic acid elevation from hepatic lipolysis.⁸ We suspect that encephalopathic episodes in AMACR deficiency are due to metabolic neurotoxicity from elevations in pristanic acid and in our case there may have been additional excitotoxicity due to recurrent focal seizures. Treatment of AMACR encephalopathy has included antiepileptics and dietary restriction of pristanic acid. Plasma exchange reduced pristanic acid levels in one case without clinical benefit.⁹ In ARD, plasma exchange reduces phytanic acid levels and may lead to clinical improvement.¹⁰

The milder transient stroke-like symptoms seen in our case and another may be the result of metabolic disturbance due to elevations in pristanic acid, although this is not proven.⁷ There were no imaging features in our case to suggest large or small vessel stroke disease or cerebral amyloid angiopathy. Furthermore, there were no convulsive seizures witnessed at the time of these episodes.

Seizures were frequently reported in AMACR deficient patients (92%), and recurrent seizures were present in half. There is limited information to guide antiepileptic drug choice. There are no reports of deleterious effects from potentially mitochondrial toxic medications in this small sample of cases.6 9 11–13 For maintenance, we still avoided drugs linked to mitochondrial toxicity.¹⁴ Lacosamide in addition to dietary changes has been associated with long-term freedom from seizures and transient neurological symptoms in our case. Others received long-term treatment with lamotrigine, lacosamide and clonazepam.^{7 15} Axonal and demyelinating neuropathies were seen in AMACR deficient patients (67%), only one was symptomatic.⁷ There were no significant signs of neuropathy in our case and nerve conduction studies were not performed. Ophthalmological findings included cataracts (33%), retinitis pigmentosa (25%), retinal pigmentary atrophy (25%) and optic atrophy (17%). Our case had glaucoma but no retinal pigmentary changes. Other neurological findings included tremor (25%), and isolated reports of ataxia, cognitive decline and spastic paraparesis. Our patient’s toe dystonia, REM behavioural disorder and central apnoea are novel features. There are isolated reports of hypogonadism, high arched palate and learning difficulties. Two patients presented with rhabdomyolysis in the context of schizophrenia or bipolar disorder (17%). It is unclear whether all these features are due to AMACR deficiency.

Progressive T2 signal change of cerebellar afferent and efferent pathways are specific for AMACR deficiency and were seen in most patients (67%).⁷ MRI findings do vary (table 1) and one patient only had cerebral atrophy.¹¹ Acute hemispheric swelling and diffusion restriction can be seen during encephalopathic episodes.

Dietary pristanic and phytanic acid restriction is widely employed for AMACR deficiency with uncertain success. Clinical outcomes were reported in nine patients (table 1). Three (33%) had satisfactory outcomes with dietary modification, two had recovered from an encephalopathic illness.^{12 13} Three (33%) were left with long-term disability after an encephalopathic illness; one followed a second encephalopathic illness despite dietary recommendations, but poor compliance was suspected. One (11%) had progressive cognitive decline without encephalopathic episodes. Two (22%) patients passed away with seemingly unrelated issues. In our case, there was a gradual decline in mobility and coordination. While we cannot exclude the possibility that her conventional vascular risk factors and age contributed to decompensation, there was no evidence of cerebral ischaemia on sequential MRI.

Conclusion

AMACR deficiency should be considered in older patients. Clinical features can include transient neurological deficits, seizures, ophthalmological abnormalities, neuropathies or febrile encephalopathy. MRI changes of the brainstem, thalami and cerebellar pathways are common. Atypical late features could include dystonic posturing, REM behavioural disorder and sleep apnoea. Treatment includes avoidance of fasting and dietary restriction of pristanic and phytanic acid. Seizures and transient neurological symptoms were treated successfully with lacosamide in our case. Comprehensive genetic testing should be considered in adults with atypical presentations.

Learning points.

• Consider peroxisomal disorders in patients with encephalopathic spells.

• Alpha-methylacyl-CoA racemase (AMACR) deficiency can show characteristic T2 high signal change of the cerebellar afferent and efferent pathways on MRI.

• AMACR deficiency can present later in life and late features could include dystonic posturing, rapid eye movement behaviour disorder and sleep apnoea.

• Lacosamide may be a suitable treatment for seizures in AMACR deficiency.

• Consider whole genome sequencing for patients with atypical clinical findings.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).