Intersection of Spinal Muscular Atrophy and Progressive Myoclonic Epilepsy Syndrome: ASAH1 Gene

Dear Editor,

Acid ceramidase deficiency manifests in two distinct clinical forms: first, as a rare lysosomal storage disorder termed Farber’s disease (FD), and, second, as an epileptic disorder known as progressive myoclonic epilepsy and spinal muscular atrophy (PME-SMA). Both disorders are the result of mutations in the ASAH1 gene, which codes for a lysosomal hydrolase that can break down the bioactive lipid ceramide.[1] SMA is characterized by the progressive loss of lower motor neurons and diffuse muscle wasting.[2] PME-SMA syndromes are non-5q SMA syndromes with the age of onset ranging from 3–15 years.[3] The disease was first described clinically by Jankovic and Rivera in 1979.[4] PME-SMA is an autosomal recessive disorder characterized by muscle weakness, wasting, and a combination of drug-resistant epilepsy and myoclonic jerks from childhood. We report one of the earliest genetically confirmed cases of PME–-SMA from India, presenting initially with symptoms of SMA at 10 years of age and later developing myoclonic jerks during the disease course.

A 37-year-old man of Indo-Aryan ethnicity was born to non-consanguineous parents and had normal development. He had insidious onset of gradually progressive difficulty climbing stairs and rising from squatting with onset at 10 years of age. The lower-limb weakness subsequently plateaued and has remained relatively static over the past 6 years. He has had difficulty in lifting heavy weights with his bilateral upper limbs for the past 6 years. He also reported a history of occasional myoclonic jerks during wakefulness but predominantly occurring at night for the past 2 years. There was no history of seizures, speech difficulties, gait imbalance, or tremors of the upper limbs. He had no history of similar illness in his family or history of similar symptoms in his family. On examination, he had intact higher mental functions with a single breath count of 45. Motor system examination showed tongue atrophy and proximal bilateral upper limb and lower limb weakness with a Medical Research Council Muscle Score of 4/5 with hyporeflexia and atrophy of proximal muscles more than distal muscles. Clinically, the patient had a lower motor neuron (LMN) type of proximal predominant symmetrical quadriparesis with myoclonic jerks. His complete blood count, renal function test, liver function test, and thyroid function tests were within normal limits. Creatine kinase was 746 IU/L (24–195 IU/L). Nerve conduction study and electromyography (EMG) showed pure motor neurogenic involvement in the cervical and lumbar segments with chronic reinnervation. Magnetic resonance imaging (MRI) of the brain was normal and muscle MRI showed severe fatty infiltration in the gluteus medius, vastus lateralis, rectus femoris, semitendinosus, semimembranosus, biceps longus, and soleus muscles [Figure 1]. Electroencephalography (EEG) showed intermittent generalized spike/polyspike and wave discharges at 3–3.5 Hz, 220 microvolts with a bifrontal maximum [Figure 2]. Whole-exome sequencing revealed a homozygous ASAH1 variant (c.124A>G; p.Thr42Ala), classified as pathogenic based on American College of Medical Genetics and Genomics criteria (PM3-strong, PM1, PM2, PM5-moderate, and PP2, PP3-supporting). Acid ceramidase activity could not be measured due to the non-availability of this test. The patient was initiated on levetiracetam 500 mg twice daily, and, after one month, there was a marked improvement in the myoclonic jerks.

Figure 1.

Axial T1 Dixon images at the level of upper (a) and lower (b) pelvis and mid-thigh (c) and mid-calf (d) region showing symmetrical end stage fat replacement of paraspinal (black arrow in a) and gluteal (black arrow in b) muscles. Medial pelvic group of muscles which include piriformis, obturators, and adductor magnus are spared (white asterisk in b). Severe atrophy and fat infiltration are seen in vastus lateralis (black arrow in c) and rectus femoris (white arrow in c). Rest of the quadriceps muscles are relatively spared. Medial compartment of thigh muscles (sartorius, gracilis, and adductor longus) appear normal (white asterisk in c). Mild involvement of posterior compartment of thigh (dashed arrow in c) is seen. Severe atrophy and end stage fat replacement is seen in the lateral head of gastrocnemius (black arrow in d). Medial head of gastrocnemius and soleus is mildly involved. Anterior compartment of lower leg (white asterisk) is spared.

Figure 2.

(a) and (b) EEG showing intermittent generalized spike/polyspike and wave discharges at 3–3.5 Hz, 220 microvolts with a bifrontal maximum in longitudinal bipolar montage. EEG: Electroencephalography

PME-SMA typically presents by the age of 2 years with progressive LMN weakness, muscle atrophy, recurrent falls, tremors, and myoclonic jerks. Such patients with PME may exhibit slow and sharp bilateral waves of 3–4 Hz on an EEG around the age of 7 years.[5] Our patient had proximal predominant LMN quadriparesis starting at age 10, later developing myoclonic jerks with generalized 3–3.5 Hz spike and wave discharges. A marked reduction or complete absence of acid ceramidase activity is typically associated with FD, whereas a milder reduction of acid ceramidase is generally associated with the PME-SMA syndrome. The activity of the acid ceramidase enzyme in FD is typically below 10%. FD represents the severe end of the disease spectrum, with onset in infancy and a median survival of approximately 3 years. The classical triad of FD is characterized by the formation of subcutaneous nodules, painful and swollen joints, and the development of a hoarse voice or aphonia.[1] Dysphonia is a hallmark feature of FD and is uncommon in SMA phenotype ASAH1-related disorders.[6]

PME-SMA is an ultra-rare disease with a prevalence of less than 1 in 1,000,000.[7] We have reviewed the phenotypic spectrum of this neurological disorder as presented in previously published cases in Supplementary Table 1. Most reported patients have disease onset before 10 years of age and present with LMN quadriparesis, with myoclonic jerks appearing later in the disease course. In contrast, Yin et al.[8] reported a case with epilepsy and marked atrophy of the cerebral and cerebellar cortex, with weakness developing 4 years later. This suggests that CNS involvement preceded peripheral nervous system (PNS) involvement. Myoclonic seizure is the most prevalent seizure type in SMA-PME, manifesting as both positive and negative myoclonia, in addition to tremors or twitches that do not elicit corresponding EEG discharges. Death resulting from respiratory complications has been observed to occur within 5–15 years following the initial onset of the disease. In the present case, despite the onset of the disease at age ten, the disease has been slowly progressive. The manifestation of myoclonic jerks was notably delayed, with no evidence of respiratory involvement till date. Filosto et al.[5] reported the first cases of SMA in adults, characterized by no myoclonic epilepsy owing to an ASAH 1 c.124A>G p.Thr 42Ala homozygous mutation in exon 2, in both siblings born of a consanguineous parentage. In addition, Puma et al.[6] described a case in which one ASAH1 allele had a similar mutation in a compound heterozygous form and presented with a Farber-like multisystem involvement with LMN involvement [Supplementary Table 1]. All of these patients had a very slow progression of symptoms, as in our case.

Supplementary Table 1.

Phenotypic and genotypic description of cases of SMA- PME

Author, year of publication	Number of patients	Age of patient	Age of onset	Sex	Consanguinity	Family history	Neuromuscular phenomenology	Systemic symptoms	DTR
Radhakrishnan et al., 2021[2]	1	6 years	2 years	M	No	No	LMN Quadriparesis with neck weakness	No	Decreased
Karimzadeh et al., 2022[3]	5	6 years	5 years	M	Yes	No	LMN Quadriparesis	No	Normal
		6 years	6.5 years	F	Yes	No	Quadriparesis	No	Brisk
		4.5 years	3.5 years	M	No	Yes	LMN Quadriparesis	No	Decreased
		15 years	7 years	M	No	Yes	LMN Quadriparesis	No	Decreased
		7 years	1.5 years	M	No	Yes	LMN Quadriparesis	Sexual hormone disturbance	Decreased
Filosto et al., 2016[5]	2	30 years	3 years	F	Yes	Yes In younger sister	LMN Quadriparesis with atrophy Proximal > Distal UL= LL weakness	No	Present
		17 years	At school age	F	Yes	Yes, sibling of 1st case	Quadriparesis with atrophy in the lower third of quadriceps and legs Proximal > Distal LL> UL	No	Brisk
Puma et al., 2021[6]	1	45 years	Childhood-onset	F	Yes	No	LMN Paraparesis Proximal	Arthralgias, reddish plaque around finger joints, alopecia, dysphonia, lipid pneumonia	NA
Najafi et al., 2023[7]	3	6 years	3 years	M	No	Yes	LMN paraparesis	No	NA
		7 years	3 years	M	Yes	No	LMN paraparesis	No	NA
		7 years	4 years	M	Yes	Yes, miscarriages in the mother	LMN paraparesis	No	NA
Yin et al., 2025[8]	1	11 years	5 years	M	No	Yes	LMN paraparesis	No	Normal
Shervin et al., 2019[11]	1	15 years	5 years	F	Yes	No	LMN Quadriparesis, Proximal > Distal	No	Decreased
Gan et al., 2015[12]	1	25 years	7 years	M	No	No	LMN Quadriparesis proximal > distal	No	Decreased
Striano et al., 2004[13]	1	12 years	4 years	M	No	No	LMN Quadriparesis with atrophy	No	NA
Yildiz et al., 2018[14]	1	13.5 years	10 years	F	Yes	Yes	LMN Quadriparesis UL>LL	No	Absent
Rubboli et al.,[15]	3	18 years	6 years	F	No	No	LMN Quadriparesis	No	NA
		8.5 years	17 months	F	No	No	LMN Quadriparesis with atrophy	No	NA
		14 years	3 years	F	No	No	LMN Quadriparesis	No	Normal
Author, year of publication	Myoclonus	Neurogenic tremors/Polyminimyoclonus	CK		EMG	MRI Brain	EEG	SMN gene Deletion	Whole exome sequencing
Radhakrishnan et al., 2021[2]	Yes	Yes	Normal		Neurogenic	Normal	Generalized polyspike and wave discharges	No	Not done
Karimzadeh et al., 2022[3]	No	No	Normal		Neurogenic	Normal	NA	Not done	Homozygous missense variant of the ASAH1 gene c.109C > A p.Pro37Thr
	No	Yes	Normal		Neurogenic	Normal	NA	No	Homozygous ASAH1 c.109C > A p.Pro37Thr
	No	No	Normal		Neurogenic	Normal	NA	Not done	ASAH1 homozygous c.125C > T p.Thr42Met
	No	Yes	NA		Neurogenic	Normal	B/L Spike and Wave discharges	NA	ASAH1 homozygous c.125C > T p. Thr42Met
	No	Yes	NA		Neurogenic	Normal	NA	NA	ASAH1 homozygous c.125C > T p.Thr42Met
Filosto et al., 2016[5]	No	Yes	Normal		Neurogenic	Normal	Normal	No	Molecular study of ASAH1 gene showed Exon 2 homozygous c.124A>G p.Thr42Ala
	No	NA	NA		Neurogenic	Normal	Normal	No	Molecular study of ASAH1 gene showed Exon 2 homozygous c.124A>G p.Thr42Ala
Puma et al., 2021[6]	No	No	NA		NA	NA	Normal	NA	NGS and Sanger Sequencing- Compound Heterozygous mutations ASAH1 pathogenic c.124A>G p.Thr42Ala 2 and c.413A>T. Mother carries first mutation
Najafi et al., 2023[7]	Yes	Yes	Normal		Neurogenic changes- Fib, PSW, and Fasc	Normal	Polyspike wave activity	No	ASAH1 c.109 C > A p.Pro37Thr, Exon 2/14, Homozygous, Missense, Likely Pathogenic
	No	No	Normal		NA	NA	NA	No	ASAH1 c.125 C > T p.Thr42Met, Exon 2/14, Homozygous, Missense, Pathogenic
	No	No	NA		NA	NA	NA	No	ASAH1 c.125 C > T p.Thr42Met, Exon 2/14, Homozygous, Missense, Pathogenic
Yin et al., 2025[8]	Yes	Yes	Normal		Neurogenic	Cerebral and cerebellar atrophy	5-7 Hz background, Interictal generalized Sharp & Sharp wave discharges	NA	Compound heterozygous variant of ASAH1, c.1157G > A p.Arg386Glu c.1188A > T p.Ter396Cysext*11
Shervin et al., 2019[11]	Yes	Yes	Normal		Neurogenic	Normal	Epileptic poly-myoclonus with generalized 2.5–3 Hz irregular sharp and slow wave complexes	NA	Homozygous mutation on ASAH-1 gene c.173C>T p. Thr58Met
Gan et al., 2015[12]	Yes	Yes	Elevated : 1000 U/L ( 35–232 U/L)		Neurogenic	Mild cerebellar atrophy	Generalized epilepsy	NA	ASAH1 One variant c.886 C > T, p.Arg296S top* Premature stop codon in exon 11, NHLBI Other variant c.456 A > C, p.Lys152Asn
Striano et al., 2004[13]	Yes	Yes	NA		Neurogenic	Normal	Diffuse theta slowing with generalized spike and polyspike and wave complexes	No	NA
Yildiz et al., 2018[14]	Yes	Yes	NA		Neurogenic	Normal	Diffuse theta slowing with generalized spike and poly spike and wave complexes	No	ASAH1 Homozygous missense c.173C > T Threonine to Methionine change at 58th position
Rubboli et al.,[15]	Yes	Yes	Elevated 398 U/L (<145 U/L)		Neurogenic	Normal	Diffuse theta slowing with generalized spike and polyspike and wave complexes	No	ASAH 1 Homozygous c.125C>T
	Yes	Yes	NA		Neurogenic	Diffuse supratentorial, sub tentorial (cerebellum) cortical atrophy and quantitative reduction of the white matter	Diffuse theta slowing with generalized spike and polyspike and wave complexes	No	ASAH1 Compound heterozygote for a frame-shift mutation c.223insC and the classical c.125C>T mutation
	Yes	Yes	NA		Neurogenic	Normal	Diffuse theta slowing with generalized spike and polyspike and wave complexes	No	ASAH 1 Heterozygous nonsense mutation c.177C>Gmat in exon 3 and a missense mutation c.456A>C.pat in exon 6

DTR: Deep tendon reflexes, CK: Creatinine kinase, EMG: Electromyography, MRI: Magnetic resonance imaging, SMN: Survival motor neuron, M: Male, F: Female, MS: Multiple sclerosis, NA: Not available, LMN: Lower motor neuron, UL: Upper limbs, LL: Lower limbs, B/L: Bilateral, NGS: Next generation sequencing, Fib: Fibrillation, PSW: Positive sharp waves, Fasc: Fasiculations

SMA-PME due to ASAH1 variants should be suspected in patients with childhood-onset progressive proximal predominant weakness along with normal early milestones and neurogenic EMG changes especially when SMN1 testing is negative. The later emergence of myoclonic jerks with ictal EEG polyspike-wave correlates, with or without generalized seizures, in the absence of early features of classic Farber syndrome (FS) further supports this diagnosis. A mixed Farber syndrome/PME-SMA phenotype has been reported in a few cases and may present with polyarticular arthritis or hoarseness in addition to progressive motor neuronopathy and later-emerging myoclonus.[9] Recent case series have further delineated the natural history of SMA-PME, showing variability in the age of onset and progression of motor neuronopathy and epilepsy, highlighting the potential role of biomarkers such as C26-ceramide levels and in-cell ceramidase activity assays for disease monitoring.[10] PME-SMA is a rare disorder that affects both the CNS and PNS. More information on the phenotypic and genotypic spectrum of the disorder may assist in the future development of enzyme replacement therapy and gene therapy for ceramidase deficiency.

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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.