Bella Italia. What a strange day. I am on “emergency duty” for the first day of kindergarten for our daughter. Since the kindergarten is a few meters down the road, I decided to stay home. However, as our windows are currently being replaced, I had nowhere to go. I ended up in a small cafe nearby that I hadn’t noticed before, which turned out to be authentically Italian. Between cornetto e cappuccino, I tried to catch up with some of my blogging duties. For quite some time, I had carried around a case report in the Orphanet Journal of Rare Diseases that I eventually managed to read. In this paper, the authors report on a sib pair with alpha-methylacyl-coA-racemase deficiency (AMACRD). Alpha what?? Exactly. I hadn’t heard of this before, either. However, what raised my interest was the phenotype of one of the patients – adult-onset focal epilepsy.
Metabolic disorders and epilepsy. Even though neurometabolic disorders are always on the differential diagnosis list when initially assessing a child with Infantile Spasms or a different epileptic encephalopathy, the frequency of these mainly recessive disorders appears to be very rare. In the large exome-sequencing studies published to date, none of the patients analyzed had a neurometabolic disorder. However, as most neurometabolic diseases are extremely rare, the phenotypic spectrum is hard to delineate. Therefore, most guidelines suggest screening for neurometabolic disorders in patients with new-onset epileptic encephalopathy. However, in adult-onset epilepsy, this is usually not performed. Haugarvoll and colleagues now report on a sib pair with focal epilepsy and additional neurological features. In both patients, recessive mutations in AMACR were identified using homozygosity mapping and exome sequencing. AMACR is the gene for the enzyme deficient in alpha-methylacyl-coA-racemase deficiency (AMACRD). Metabolic testing showing marked elevation of pristanic acid confirmed this diagnosis.
The phenotype. Haugarvoll and colleagues report on two siblings with focal epilepsy and other neurological features. Neither patient had symptoms until their thirties. Patient A developed peripheral neuropathy and cataracts in his forties, followed by an episode of unexplained encephalopathy with cerebral edema, which resulted in visual loss as a residual feature. Shortly after this, the patient developed focal epilepsy with complex partial seizures. He died at the age of 51 due to liver cancer. The constellation of these symptoms did not point towards a specific syndrome at this point. His sister developed focal epilepsy at the age of 33, followed by mild tremor. At the age 53, the patient also had acute encephalopathy with lack of speech (aphasia) and weakness of her right arm. She was found to have left-sided cerebral edema, but the cause remained unknown. A few years later, the patient was also diagnosed with peripheral neuropathy. The focal seizures persisted, but improved on lamotrigine.
The peroxisome. Hydrogen peroxide is the active ingredient in bleach. It has a very strong oxidizing capacity and readily donates one or more of its oxygen molecules to other molecules in a chemical reaction. Peroxisomes are cellular organelles capable of producing peroxides for us in biochemical reactions. Peroxisomes, just like mitochondria, are independent organelles that replicate by themselves. However, in contrast to mitochondria, they do not contain DNA. All peroxisomal proteins are imported into these organelles. In human, peroxisomes are mainly important in two biochemical pathways. First, they are important for breaking down fatty acids, particularly long and branched chainfatty acids. In addition, peroxisomes play an important role in the synthesis of so-called plasmalogens, a particular type of phospholipid that is highly concentrated in myelin sheaths. Accordingly, peroxisomal disorders may result in abnormalities of myelination. The most severe human peroxisomal disorder is Zellweger Syndrome, where the biogenesis of peroxisomes is impaired. Patients are found to have “empty peroxisomes” on electron microscopy. Clinicially, Zellweger Syndrome presents as neonatally with muscular hypotonia, seizures and apnea. Patients often also have other additional abnormalities including cerebral malformations, an enlarged liver (hepatomegaly) and renal cysts. Zellweger patients often have a high forehead and various craniofacial abnormalities. Myelination is often delayed or underdeveloped (hypomyeliniation). Zellweger Syndrome demonstrates the importance of peroxisomes in the cellular metabolism.
AMACR. In contrast to Zellweger Syndrome, alpha-methylacyl-coA-racemase deficiency (AMACRD) does not affect the overall function of the peroxisome, but only a single metabolic step in the breakdown of branched chain fatty acids. Two of these fatty acids, phytanic acid and pristanic are derived from regular food sources including meat and dairy. AMARCD was initially identified in 2000 as a metabolic disorder mainly causing sensory-motor neuropathy. Very few patients have been described since. The report by Haugarvoll and colleagues now describes a sib pair with adult-onset AMACRD. Even though neuropathy was present in both patients, focal seizures were the leading feature in one of the siblings.
Lessons for EuroEPINOMICS. Metabolic disorders are usually inherited in a recessive fashion. The plethora of metabolic disorders known in man including their atypical presentations is virtually impossible to comprehend. Therefore, high-throughput genomic technologies are likely to increasingly discover these disorders through a “genetics-first” approach. The next few years will tell whether atypical presentations such as the case presented by Haugarvoll and colleagues are a recurrent cause of human epilepsy. Either way, as some metabolic disorders can be treated through dietary modification, it will be important to keep an open mind regarding these diseases. In the case of AMACRD, dietary restriction of phytanic acid and pristanic acid may help reduce symptoms.