An unusual case of a toddler with Canavan disease with frequent intractable seizures: A case report and review of the literature

Abstract

Canavan disease is a rare fetal inherited leukodystrophy, caused by accumulation of N-acetyl-aspartate in the brain. Here, we report a child presented with frequent intractable seizures and visual impairment. A 14-month-old female infant with a complaint of the absence of neck holding and generalized tonic-clonic seizures was referred to our hospital. Macrocephaly, setting sun eyes, tremor, and hypotonia were observed. Funduscopy showed optic atrophy. Our patient’s flash visual evoked potential showed blindness. Her brain magnetic resonance imaging showed diffuse white matter in subcortical, basal ganglia, and dorsal pons. Electroencephalography showed diffuse slow and sharp waves. The genetic study detected a hemizygous mutation in the aspartoacylase gene. Our patient was diagnosed with Canavan disease and began anticonvulsant treatment. However, seizures were not under control. Then, her medications were discontinued, and clobazam and primidone were administered. In conclusion, starting clobazam and primidone may help prevent frequently intractable seizures in Canavan disease patients.

Introduction

Canavan disease (CD) is an autosomal recessive leukoencephalopathy, which mostly presents in early infancy. The mutations in aspartoacylase (ASPA) gene which encodes ASPA enzyme cause accumulation of N-acetyl-aspartate (NAA) that may induce myelin damage in oligodendrocytes.^1,2 CD appears as diffuse white matter involvement in the brain magnetic resonance imaging (MRI), mostly in subcortical areas, basal ganglia, and dorsal pons. ³ The patients show symptoms in early infancy with impaired vision, macrocephaly, hypotonia, and abnormal psychomotor and intellectual development. ⁴

To date, no effective treatment has been provided for this disease, and the current treatment for patients suffering from CD is supportive. ⁵ Gene therapy has been presented as a promising method in recent years to treat CD. Nonetheless, challenges such as the ability to detect the disease at a young age make it difficult to succeed on this path. ⁶ Intractable and difficult-to-treat seizures are a rare but challenging feature of the disease. Few publications have mentioned a patient with CD who suffers from recurrent seizures that are not controlled well by common medications.^7–9 Our ability to manage the seizures of CD patients would be enhanced if we could identify effective drug regimens for these patients.

Herein, we report a case of a CD patient with characteristic MRI findings who had severe visual impairment and frequent difficult-to-treat seizures, which showed up early in the disease course.

Case

A 14-month-old female infant was admitted to our clinic for investigating possible neurodegenerative diseases. She was born by elective cesarean section at 36 weeks gestational age in an uncomplicated pregnancy. Apgar score was 9–10. She had a birth weight of 3360 g, head circumference of 34 cm, and height of 51 cm. She is the first child of non-consanguineous parents and her mother had two previous pregnancies which resulted in abortion. Her family had a middle-class income. Her father works in the rubber industry and her mother is a housewife. At the time of birth, her mother’s and father’s age were 25 and 29 years, respectively. There was no familial history of hereditary and metabolic diseases in the two previous generations of the child.

The infant’s growth was normal and she successfully had reached developmental milestones until the age of 2 months. At 2 months, the parents noticed she was unable to hold her neck and gradually developed lethargy. At 3 months, she showed first episodes of seizure. Based on the history taken from her parents, the seizures were generalized tonic-clonic (GTC) ¹⁰ ; there were episodes of stiffening and rhythmic jerks in her bilateral limbs that decreased in frequency in the course of seizure which lasted approximately 3 min with impaired awareness. Different dosages of sodium valproate, ranging from 20 to 30 mg, were ineffective in completely controlling seizures.

At the age of 14 months, the child’s parents were referred to our clinic due to the absence of neck holding and frequent intractable seizures. She was admitted to our hospital for further evaluation.

At the time of admission, physical examination revealed macrocephaly with the head circumference of 47.2 cm, height of 78 cm, and weight of 10 kg; setting sun eyes; tremor; and hypotonia. The funduscopic examination revealed optic atrophy. Examinations of other cranial and peripheral nerves were normal. Face was symmetric with no facial dysmorphic features (Figure 1).

Figure 1.

Patient’s appearance with setting sun eyes, macrocephaly, and symmetrical face.

The pediatrician of our team ordered a flash visual evoked potential (FVEP), brain MRI, and an electroencephalography (EEG) for the infant. The FVEP revealed bilateral abnormal P100 latencies and no obvious waves in the both eyes, demonstrating that our patient was totally blind (Figure 2). Her brain MRI reported diffuse white matter T2 hyper-intensity and T1 hypo-intensity in the periventricular, juxtacortical, and subcortical white matter with posterior brain stem, putamen, bilateral thalami, and cerebellum white matter involvement. Moreover, prominent Virchow–Robin Spaces (VRS) were seen (Figure 3). EEG demonstrated diffuse slow and sharp waves (Figure 4).

Figure 2.

Flash visual evoked potential revealed bilateral abnormal P100 latencies and no obvious waves in the both eyes.

Figure 3.

Magnetic resonance imaging showing diffuse white matter T2 hyper-intensity in brain and brain stem (black arrows).

Figure 4.

Electroencephalography demonstrated diffuse slow and sharp (black arrows) waves.

Leukodystrophies such as Krabbe disease, mucopolysaccharidosis, and mitochondrial diseases were suspected. Therefore, the genetic study was performed by next-generation sequencing (NGS) method and the result was confirmed by the Sanger sequencing method. The homozygous c.914C>A (p.Ala305Glu) variant in the ASPA gene, which is pathogenic based on American College of Medical Genetics and Genomics (ACMG) ¹¹ classification, was found. Mutations in this gene result in CD. In due course, our patient was diagnosed with CD and started receiving multivitamins and anticonvulsant drugs such as phenytoin 18 mg every 12 h (5 mg/kg), levetiracetam 0.8 mg every 3 h (30 mg/kg), and phenobarbital 20 mg every 12 h (5 mg/kg). She was discharged with stable vital signs and good clinical condition.

During the 2-month post-discharge follow-up, the seizures were not controlled by the prescribed anticonvulsants and this was the most challenging part of her treatment. Her drugs were discontinued and we started primidone 188 mg daily (15 mg/kg), clobazam 10 mg every 12 h, and vitamin B6 40 mg daily. We were able to terminate her seizures with this drug regimen successfully. After a 3-month follow-up, at the age of 20 months, the patient’s seizures were completely under control, and symptoms such as tremor and hypotonia had improved to some extent.

Discussion

CD is a rare hereditary leukodystrophy, which is caused by ASPA deficiency. This occurs by a mutation in the ASPA gene resulting in accumulation of NAA in the brain. The ASPA gene provides instructions for making an enzyme called ASPA. In the brain, this enzyme breaks down NAA into aspartic acid and acetic acid. Patients with CD are prone to seizures, which can be difficult to control as in our patient. Our patient started having GTCs at the age of 3 months. Despite receiving various anticonvulsants, her seizures were not terminated. A study by Yalcinkaya et al. revealed that affected children might experience intractable seizures as one of the first presentations of the disease, similar to our case. They reported two mutations in their patients’ genes: c.914C>A; p.Ala305Glu and c.863A>G; p.Tyr288Cys. As mentioned, the first mutation is similar to the mutation found in our patient. ⁸ Contrary to a study by Bley et al., ¹² which presented increased seizure prevalence in the patients over the first decade of the life and not in the first year, our patient showed seizure as one of the first presentations of the CD during the first months of her life. Delaney et al. ⁹ reported a CD patient presenting with stroke-like symptoms at first and concomitant recurrent seizures which were controlled in the first year of life; after weaning off antiepileptic drugs, the seizures reappeared in the later disease course.

Most patients may appear normal during the first few months of life; however, careful examination usually reveals neurological abnormalities, hypotonia, and visual impairment. Diagnostic modalities in our patient showed a completely blind condition.

Various factors can cause vision problems in these patients such as optic nerve atrophy, retinal degeneration, and impaired visual pathways to the visual cortex caused by the damage to the white matter and nerve myelin.^13,14 Benson et al. ¹⁵ discovered retinitis pigmentosa-like findings in a CD patient causing progressive vision loss that was first thought to be due to optic nerve atrophy. Our patient had macrocephaly with setting sun eyes, which is among the common abnormal findings in CD. However, previous studies have also reported microcephaly in the cases of CD. ¹⁶

Our challenge with this patient was that the patient’s seizures were resistant to the initial treatments and recurring. In the review of past studies, few CD cases had seizures that were resistant to various anticonvulsants. Drugs such as valproate, levetiracetam, and phenobarbital were among the effective choices.^7,9 However, in our patient, these drugs were not effective in the long-term management of the seizures and changing the anticonvulsant regimen to primidone and clobazam controlled the intractable symptoms of the patient at last, which was a promising point in the course of the disease.

Although CD infants are usually born from relative parents,^3,17 our patient was born from non-relative parents which revealed that this risk should be considered in a non-consanguineous family as well.

In 2015, Nguyen and Ishak ¹⁸ reported a characteristic finding in CD patients. In imaging studies, CD usually affects the white matter in a diffuse and symmetrical pattern. The characteristic appearance is initial subcortical white matter involvement, along with subsequent centripetal progression. Reduced diffusion without any contrast enhancement is noticed in the affected white matter. Similarly, in our case, white matter involvement was reported in the periventricular, juxtacortical, and subcortical areas. One specific finding in the MRI of our patient was prominent VRS that are fluid-filled perivascular spaces. Bhat et al. ¹⁹ reported a CD patient with cribriform white matter and VRS-like patterns, as in our patient.

Over 40 mutations in the ASPA gene have been discovered in various groups. ⁸ Two mutations in the ASPA gene, C693A and A854C, account for more than 98% of the CD patients in Ashkenazi Jewish people. Our patient had the c.914C>A (p.Ala305Glu) variant which is considered pathogenic and confirms the diagnosis. This mutation is a common one among non-Jewish population and is associated with both mild and severe cases of CD.^4,20

Conclusion

In this report, we represented a 14-month-old girl with CD which is an autosomal recessive leukodystrophy associated with a mutation in the ASPA gene. The lessons learned from this case suggest that it is useful to evaluate infants with poor neck holding, impaired vision, and frequent intractable seizures for the presence of any undiagnosed neurogenetic disorder such as CD. In addition, CD should be considered even in non-consanguineous parents. Data derived from metabolic analyses, brain MRI, and genetic study will help physicians to find an early diagnosis that will improve the patient’s quality of life. Seizure treatment is rarely ineffective and necessitates thorough patient monitoring. Also, starting clobazam and primidone early may help prevent frequently intractable seizures in CD patients. However, further research is needed to reach more specific conclusions.