Dr.Terencia.A/ Dr. Sheela Nampoothiri,DrDhanya (ped genetics)Dr.Vinayan/Dr.Vaishakh Anandped Neuro)Dr. C Jayakumar
Eight years old male child, 1 st born to NCM presented with paroxysmal events since last 6 months, gaze disturbance and hard of hearing since 2 weeksduration.
Perinatal and developmental history are normal but had seizures at the age of 1.5 years with fever and seizure free until 7.5 years.Six months back child had fever and seizure. MRI brain was taken and showed posterior predominant signal alterations involving the periventricular and deep white matter in the parietal occipital region along with involvement of posterior temporal region,splenium, posterior edge of IC and lateral posterior midbrain and pons with trillayered appearing signal contrast enhancement near the leading edge of lesion s/o X linked Adrenoleukodystrophy.
EEG done was normal.
Child was started onAEDs.
On evaluation WES done showed WES – ABCD1- hemizygous – exon 3 ALD x linked recesive – pathogenic On further evaluation ACTH -359 (high) with cortisol random – 5.47(low).
Child was started on steroids(Hisone) in view of adrenal insufficiency and AEDs were continued. But since mother noticed some gaze disturbances(outward gaze in left gaze) with increased paroxysmal events, memory issues, comprehension difficulties and hearing loss, child was brought here for further evaluation and management.
On examination child was alert, playful with stable Vitals. He had microcephaly, Coarse facies, Hyperpigmented knuckles with no neurocutaneous markers
Systemic examination showed appendicular hypotonia with difficult to elicit DTR.
There were No cerebellar signs or involuntary movements.
Differential Diagnosis-
1.Leukodystrophy in ALD
2.Myeloneuropathy
3.Adrenal Insufficiency
Labs TC-8.5ku/ml, Hb-13.9g/dl, Plt-317ku/ml, Na-138mmol/L, S.K-4.2mmol/L
Figure1,2,3 and 4:- MRI brain with contrast showed confluent and symmetric bilateral hyperintensities without diffusion restriction in white matter of the parieto-occipital regions, posterior body and splenium of corpus callosum, acoustic radiation, lateral leminiscus, pons, cerebellar peduncle. Peripheral diffusion restriction and post contrast enhancement, scattered areas of gradient blooming in the subsequent region.
Visual evoked potential , BERA and Nerve conduction were normal.
Retina normal fundus and macula in both eyes.
Genetics consult
As mother is a carrier with younger boy unaffected, hence risk to have another affected child is 25% and prenatal diagnosis can be offered at 12 weeks of gestation in next pregnancy. In view of adrenal insufficiency he was started on hydrocoticisterone
Requirement of stress dosing of steroids was explained to parents.
During the course of hospital stay, he had no adverse events. Current clinical condition of the child was explained to parentsand was advised to keep a close follow up.
Adrenoleukodystrophy (ALD) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues.
It is an X-linked genetic disorder caused pathogenic variants in the ABCD1 gene.
ALD consists of a spectrum of clinical syndromes (including leukodystrophy, myeloneuropathy, and adrenal insufficiency) that vary in the age and severity of clinical presentation.
ALD in males – Affected males have (combinations of) several clinical syndromes and can present from childhood through adulthood:
Leukodystrophy – Affected boys typically present between four and eight years of age with learning disabilities and behavior problems, followed neurologic deterioration that includes increasing cognitive and behavioral abnormalities, blindness, and the development of quadriparesis. Approximately 20 percent of affected individuals have seizures. Approximately 10 to 15 percent have arrested ALD, characterized absence of symptom progression and lack of lesion growth or enhancement on brain MRI; a minority of these patients undergo stepwise progression or conversion to progressive childhood leukodystrophy.
•Myeloneuropathy – Myeloneuropathy typically presents in adult males between 20 and 40 years of age. The primary manifestation is spinal cord dysfunction with progressive stiffness and weakness of the legs (spastic paraparesis), abnormal sphincter control, neurogenic bladder, and sexual dysfunction. Polyneuropathy is also a common feature, presenting with numbness or painful paresthesias, which contribute to gait abnormalities. Most individuals have adrenal insufficiency. Myeloneuropathy may also present as a progressive cerebellar disorder.
•Adrenal insufficiency – Primary adrenal insufficiency is the initial manifestation of ALD in 30 to 40 percent of patients and remains the only sign of ALD in approximately 8 to 10 percent. In most affected patients, adrenal insufficiency presents before the age of 10 years, but it can present later. Most patients with isolated adrenal insufficiency go on to develop myeloneuropathy mid-adulthood.
●Females – Female patients often develop myeloneuropathy and polyneuropathy symptoms during adulthood. The frequency of symptoms rises from <20 percent in females under 40 years of age to almost 90 percent in females older than 60 years.
●Newborn screening – For ALD, newborn screening is available in some states in the United States and several other countries. If the newborn screen is positive, follow-up confirmation testing should be completed as soon as possible.
●Laboratory testing – Measuring VLCFA levels is the first step. The plasma concentration of VLCFAs is elevated in nearly all males with the ALD. If elevated VLCFA levels are detected, confirmatory genetic testing is performed. In addition, adrenal function testing should be performed at the time of diagnosis and re-evaluated yearly.
●Imaging – All male individuals with confirmed ALD complex should undergo neuroimaging with brain MRI at the time of diagnosis. Brain MRI is normal before onset of leukodystrophybut is abnormal in symptomatic males with leukodystrophy, demonstrating demyelination in cerebral white matter. In patients with myeloneuropathy, MRI of the spinal cord is normal (although atrophy of the cervical spinal cord becomes apparent in advanced disease). Presymptomatic boys with childhood ALD who initially have normal MRI should undergo follow-up imaging every 6 to 12 months
TAKE HOME MESSAGE-
Although adrenoleucodystrophy is a rare disease, it is the most common peroxisomal disorder.X-linked adrenoleukodystrophy is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues. Patients with ALD are asymptomatic at birth, but during life, adrenal insufficiency,leukodystrophy, and myeloneuropathy occur. Primary adrenal insufficiency is the initial manifestation of ALD in 30 to 40 percent of patients. Unlike autoimmune adrenal insufficiency, the adrenal insufficiency of ALD is usually characterized glucocorticoid deficiency only, while mineralocorticoid function is preserved. Prompt evaluation for ALD is warranted in boys presenting with primary adrenal insufficiency, particularly if antiadrenal antibodies are negative. Early diagnosis may improve outcomes from hematopoietic stem cell transplantation
