A child of congenital muscular dystrophy-dystroglycanopathy with a novel variant in the CRPPA gene: a case report and literature review

Abstract

Background

Dystroglycanopathy is a genetically heterogeneous group of rare muscular dystrophies that affect the brain, muscles, and eyes, primarily resulting from impaired glycosylation of α-dystroglycan. In this study, we identify and characterize a novel heterozygous CRPPA gene variant causally associated with α-dystroglycanopathy.

Case Description

We present a case of a 1-year and 5-month-old female with elevated creatine kinase (CK) levels and seizures, along with global developmental delay, microphthalmia, hypotonia, and myasthenia. Notably absent was ocular involvement. The serum CK levels typically fluctuated between 2,356 and 9,555 U/L. Video-electroencephalogram monitoring demonstrated abnormal discharge in the left anterior frontal region. Brain magnetic resonance imaging revealed numerous subcortical cysts in the bilateral cerebellar hemispheres and corpus callosum dysplasia. We performed whole-exome sequencing to identify compound heterozygous mutations in the CRPPA gene [Online Mendelian Inheritance in Man (OMIM): 614643]. The identified mutations include the pathogenic variant c.1251G>A (p. Gln 417=) inherited from father, and the c.1119+2T>G variant inherited from mother. We confirm that c.1119+2T>G was a novel splice-site variant. Based on the clinical manifestations, ancillary tests, and genetic results, the patient was diagnosed with congenital muscular dystrophy with mental retardation (CMD-MR). Levetiracetam effectively controlled the seizures. However, the patient’s motor and cognitive impairments remained unaddressed by pharmacological interventions and persisted backward.

Conclusions

We present a case of α-dystroglycanopathy caused by a novel splice site variant, c.1119+2T>G, in the CRPPA gene. The patient presented with clinical features characteristic of CMD-MR, thus extending the phenotypic spectrum of α-dystroglycanopathy.

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Key findings

• This case report describes a novel variant (c.1119+2T>G) in the CRPPA gene of an α-dystroglycanopathy patient.

What is known and what is new?

• Dystroglycanopathy is a group of disorders characterized by genetic and phenotypic heterogeneity, affecting the brain, muscles, and eyes, mainly due to defective glycosylation of α-dystroglycan. Eighteen pathogenic genes have been implicated in α-dystroglycanopathies, with the CRPPA (ISPD) gene ranking second.

• We report a novel variant in the CRPPA gene of α-dystroglycanopathy, thereby expanding the phenotypic spectrum of the disease.

What is the implication, and what should change now?

• The discovery of a novel variant in the CRPPA gene enhances our understanding of α-dystroglycanopathy. Future research should focus on functionally validating the effect of c.1119+2T>G, which could further advance studies on the genotype-phenotype correlation.

Introduction

Congenital muscular dystrophy (CMD)-dystroglycanopathy is a rare disorder caused by defective glycosylation of dystroglycan, affecting the brain, muscle, and eyes, resulting from impaired glycosylation of dystroglycan (1). Dystroglycan has two subunits, α-dystroglycan (α-DG) and β-dystroglycan, with α-dystroglycanopathy being the most common. To date, 18 pathogenic genes have been associated with α-dystroglycanopathies (2), with the CDP-L-ribitol pyrophosphorylase A (CRPPA; also known as ISPD) gene ranking second (3). The CRPPA gene on chromosome 7p21.2 spans 334 kb and comprises 10 exons that encode a 451-amino-acid cytidyltransferase enzyme. This enzyme is pivotal in the biosynthesis of CDP-ribitol, which FKTN and FKRP subsequently employ for the transfer of ribose-phosphate groups to α-DG (4). The biallelic loss of the CRPPA gene indirectly impacts the glycosylation of α-DG and leads to α-dystroglycanopathies (5).

α-dystroglycanopathies exhibit genetic heterogeneity, encompassing a wide range of clinical phenotypes, from the lethal Walker-Warburg syndrome (WWS) to the mild form of limb-girdle muscular dystrophy (LGMD). Individuals in the same family with identical genetic variants may present distinct clinical phenotypes (6). Few cases of CMD with mental retardation (CMD-MR), as an intermediate phenotype, have been reported to date. Although the pathogenic mechanisms of CRPPA have been elucidated, a clear genotype-phenotype correlation has yet to be established and warrants further investigation.

In this study, we describe a novel variant in the CRPPA gene identified in a child. The patient exhibited a clinical phenotype consistent with CMD-MR, enhancing the understanding of the genotype-phenotype correlation in α-dystroglycanopathies. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-6/rc).

Case presentation

We present a case of a 1-year and 5-month-old girl who exhibited elevated creatine kinase (CK) levels at birth and developed seizures at 1 month of age. Convulsions predominantly presented as repetitive shaking of a single upper or lower limb, occurring 3 to 4 times daily. Physical examination of the child revealed global developmental delay, adequate subcutaneous fat, adducted thumbs, small palpebral fissures, a short interpupillary distance, and limb hypotonia. Laboratory findings showed that serum CK levels typically fluctuated between 2,356 and 9,555 U/L, with significant elevations reaching 54,136 U/L during periods of stress. Interictal video-electroencephalography (VEEG) monitoring revealed sharp waves, multi-spikes, and slow waves predominantly over the left frontal region. During the ictal phase, multifocal discharges were observed in the left anterior region. Brain magnetic resonance imaging (MRI) demonstrated numerous subcortical cysts in the bilateral cerebellar hemispheres and corpus callosum dysplasia (Figure 1). The child was a G2P2, delivered at term by cesarean section due to maternal diabetes during pregnancy, with a birth weight of 4.25 kg. He demonstrates instability in head control and is not yet capable of verbal communication. The parents are non-consanguineous and healthy, with a history of one first-trimester miscarriage. There is no family history of hereditary disorders.

Figure 1.

Brain MRI findings. (A,B) Brain MRI shows multiple cysts in the cerebellum (red arrows), and (C) dysplasia of the corpus callosum (red arrow). MRI, magnetic resonance imaging.

Trio whole-exome sequencing (WES) identified two variants in CRPPA gene [NM_001101426.4:exon9:c.1251G>A (p.Gln417Gln) and NM_001101426.4:intron8:c.1119+2T>G] in the proband, resulting in a compound heterozygous state, with the father and mother being heterozygous carriers of c.1251G>A (p.Gln417Gln) and c.1119+2T>G respectively (Figure 2). The synonymous variant c.1251G>A (p.Gln417Gln) was absent in the gnomAD v4.1.0 database (PM2_Supporting). Multiple splicing prediction algorithms (dbscSNV_ADA_SCORE =0.997, dbscSNV_RF_SCORE =0.920, SpliceAI =0.510) consistently suggest this variant may disrupt the consensus donor splice site in CRPPA intron 9. Reverse transcription polymerase chain reaction (RT-PCR) analysis of messenger RNA (mRNA) confirmed this splicing alteration (PP3) (7). This variant has been reported in the literature in individuals affected with CRPPA-related conditions, five unrelated propands with CMD with confirmed compound heterozygous CRPPA mutations, c.1251G>A/c.789+2T>G, c.1251G>A/c.990delC, c.1251G>A/c.1186G>T, c.1251G>A/c.659A>T, c.1251G>A/exon6-9del (7) (PM3_VeryStrong). According to American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) guidelines, the variant is classified as pathogenic (PM2_Supporting + PM3_VeryStrong + PP3). The c.1119+2T>G was absent in the gnomAD v4.1.0 database (PM2_Supporting) and has not been reported to our knowledge. This variant is located in intron 8, and its adjacent exon 8 has 93 bp, predicted to likely escape NMD (nonsense-mediated mRNA decay) but may result in a truncated protein of <10%. No pathogenic missense variants have been reported within this exon so far (PVS1_Moderate). The variant was detected in compound heterozygosity with the pathogenic variant c.1251G>A (p.Gln417Gln) (PM3). According to ACMG/AMP guidelines, the variant is classified as VUS (PVS1_Moderate + PM2_Supporting + PM3).

Figure 2.

The figure shows the genetic segregation of variants of the CRPPA gene variants. (A) Family pedigree. Circles represent females, and squares represent males. Filled symbols designate the proband. (B) Sanger sequencing confirmed the mutation in the family. c.1251G>A from father and c.1119+2T>G from mother.

The diagnosis of CMD-MR was established based on characteristic clinical features (muscle weakness, hypotonia, normal ocular structure), markedly elevated serum CK levels, neuroimaging findings (cerebellar subcortical microcysts and corpus callosum dysgenesis), electroclinical evidence of focal epilepsy, and the identification of biallelic pathogenic variants in the CRPPA gene. The patient was treated with levetiracetam (25 mg/kg/day) from 1 month of age, achieving seizure-free status. Follow-up VEEG demonstrated a reduction in interictal discharges, with no seizures observed. Levetiracetam was discontinued at 1 year of age without medical supervision, and the patient remained seizure-free. No specific intervention has been provided for the developmental delay, which has not improved.

All procedures performed in this study were in accordance with the ethical standards of Institutional Review Board of The Second Hospital of Shandong University (approval No. KYLL-2022D017) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The pathogenesis of α-dystroglycanopathy is attributed to impaired glycosylation of α-DG. α-DG primarily functions to link the dystrophin-glycoprotein complex to extracellular matrix proteins, thereby stabilizing muscle structure and function (2). Loss of α-DG glycosylation in muscular dystrophies disrupts its linkage to extracellular proteins, thereby contributing to disease pathogenesis. It is currently believed that 18 genes are associated with α-dystroglycanopathy. FKRP (8), POMGNT1 (9), and POMT1 (10) are recognized as the most common pathogenic genes for α-dystroglycanopathy in Europe and Asia. With the identification of new variants, the CRPPA gene has emerged as the second frequent cause.

In this study, we report a case of α-dystroglycanopathy caused by compound heterozygous mutations in the CRPPA gene, one of which is a novel variant. The c.1251G>A is a synonymous variant inherited from her father, which affects splicing. RT-PCR analysis of mRNA has confirmed this splicing alteration (7). This variant has thus far been reported exclusively in the Chinese population and is regarded as a hotspot mutation within this population (1,11). The c.1119+2T>G is a classic splice site variant inherited from her mother, which has not been reported to our knowledge. The ACMG predicted the variant escapes NMD and may produce a truncated protein (<10%). Although the pathogenicity of the c.1119+2T>G remains unvalidated by functional assays, the adjacent c.1120-1G>T variant is pathogenic, confirmed by CRPPA complementation in fibroblasts (12).

α-dystroglycanopathies exhibit considerable genetic heterogeneity. However, the mechanism between genotype and clinical phenotype remains unclear. To date, only nine cases of CMD-MR have been reported (1,9,13-16). Our case involves both muscular and cerebral involvement, with no ocular manifestations. She exhibits significant impairment in both motor and intellectual functions. The clinical phenotype strongly supports a diagnosis of CMD-MR, further contributing to the growing case series of CMD-MR. In addition, we have compiled 72 mutation sites of 63 cases, including the new variation we identified (Table 1). We find cases carrying either a missense, synonymous, or in-frame variant were more frequently associated with milder LGMD phenotypes (21/45), while those lacking such variants predominantly presented with severe WWS (13/18). The pathogenicity of variants is correlated with the extent of protein dysfunction. Mutations in the C-terminal cytidyltransferase domain, especially truncating mutations, are more likely to reduce enzyme activity and result in disease. For example, c.1114_1116del (p.Val372del) causes a mild phenotype due to the loss of a single C-terminal residue, while c.1186G>T (p.Glu396*) leads to a larger C-terminal deletion, resulting in a more severe phenotype (33). In our case, the c.1251G>A and c.1119+2T>G variants are likely to impact the C-terminal cytidyltransferase domain, potentially contributing to CMD-MR. However, further functional validation is needed to confirm these findings.

Table 1. The gene variants corresponding to the different phenotypes of CRPPA.

Group	Variant 1					Variant 2				Disease	Article
	Location	Exon	Protein	Origin		Location	Exon	Protein	Origin
Group 1 (n=45)	c.5A>T	1	Glu2Val	Mother		c.505A>T	2	Lys169*	Father	MEB	Song et al. (1)
	c.79A>C	1	Thr27Pro	Novel		c.1218T>G	9	Ile406Met	Novel	LGMD	Wu et al. (17)
	c.157G>A	1	Ala53Thr	NA		c.1183A>T	9	Arg395*	NA	LGMD	Cirak et al. (18)
	c.161G>T	1	Gly54Ala	Mother		c.161G>T	1	Gly54Ala	Father	LGMD	Tasca et al. (19)
	c.277-279del	2	Ile93del	NA		c.789+2T>G	–	–	NA	WWS	Willer et al. (12)
	c.340C>G	2	His114Asp	Mother		c.340C>G	2	His114Asp	Father	CMD without MR	Song et al. (1)
	c.346C>T	2	Arg116Cys	NA		c.947C>A	7	Thr316Lys	NA	LGMD	Sframeli et al. (9)
	c.364G>C	2	Ala122Pro	Mother		c.802C>T	5	Arg268*	Father	MEB	Roscioli et al. (3)
	c.367G>A	2	Gly123Arg	Mother		c.367G>A	2	Gly123Arg	Father	LGMD	Baranello et al. (6)
	c.377G>A	2	Arg126His	Mother		c.53dup	1	Ser19Glufs*97	Father	WWS	Cirak et al. (18)
	c.377G>A	2	Arg126His	NA		c.2T>G	1	Met1Arg	NA	LGMD	Sframeli et al. (9)
	c.377G>A	2	Arg126His	NA		c.2T>G	1	Met1Arg	NA	CMD-MR	Sframeli et al. (9)
	c.446C>T	2	Pro149Leu	NA		c.643C>T	3	Gln215*	NA	CMD without MR	Cirak et al. (18)
	c.457A>T	2	Ile153Phe	NA		–	6-9del	–	NA	LGMD	Song et al. (1)
	c.458T>C	2	Ile153Thr	Novel		c. 535-3C>G	–	–	Novel	CMD without MR	Ceyhan-Birsoy et al. (20)
	c.464A>G	2	His155Arg	Father		c.712A>G	4	Thr238Ala	Mother	CMD-MR	Song et al. (1)
	c.550C>T	3	Arg184Gly	Mother		c.984G>T	7	Glu328His	Father	LGMD	Yang et al. (21)
	c.538G>A	3	Ala180Thr	NA		c.538G>A	3	Ala180Thr	NA	LGMD	Song et al. (1)
	c.605C>T	3	Ser202Leu	NA		c.165dup	1	Cys56Valfs*60	NA	LGMD	Johnson et al. (22)
	c.613C>T	3	Arg205Cys	Father		c.747C>A	4	Cys249*	Mother	CMD-MR	Chen et al. (15)
	c.614G>A	3	Arg205His	Mother		–	9-10del	–	Father	WWS	Czeschik et al. (23)
	c.641C>T	3	Pro214Leu	NA		chr7:16312789-16323521del	–	–	NA	WWS	Alharbi et al. (24)
	chr7:16415756T>G	3	Gln215His	Father		chr7:16415756T>G	3	Gln215His	Mother	CMD-MR	Biswal et al. (13)
	c.647C>A	3	Ala216Asp	Mother		c.647C>A	3	Ala216Asp	Father	WWS	Roscioli et al. (3)
	c.659A>G	3	Asp220Val	Mother		c.1251G>A	9	Gln417 =	Father	CMD without MR	Song et al. (1)
	c.676 T>C	3	Tyr226His	NA		c.836-5T>G	–	–	NA	LGMD	Magri et al. (25)
	c.677A>G	3	Tyr266Cys	NA		c.53dup	1	Ser19Glufs*97	NA	LGMD	Cirak et al. (18)
	c.1104-1106del	8	V372del	Novel		c.1270del	10	Glu424Argfs*3	Novel	LGMD	Hu et al. (26)
	c.1106T>G	8	Val369Gly	Mother		c.674del	3	Ala225Aspfs*21	Father	WWS	Chen et al. (15)
	c.1114-1116del	8	Val373del	NA		c.1183A>T	9	Arg395*	NA	LGMD	Cirak et al. (18)
	c.1114-1116del	8	Val373del	Mother		c.1114-1116del	8	Val373del	Father	LGMD	Tasca et al. (19)
	c.1114-1116del	8	Val373del	NA		c.1027-10G>A	–	–	NA	LGMD	Song et al. (1)
	c.1114-1116del	8	Val373del	Mother		c.1026+1G>A	–	–	Father	LGMD	Song et al. (1)
	c.1114-1116del	8	Val373del	NA		c.1354T>G	10	*452Arg	NA	LGMD	Westra et al. (27)
	c.1124A>G	9	His375Arg	Mother		c.1026+1G>A	–	–	Father	LGMD	Song et al. (1)
	C.1231C> T	9	Leu411Phe	Father		–	9del	–	Mother	LGMD	Huang et al. (28)
	c.1251G>A	9	Gln417 =	Father		c.1119+2T>G	–	–	Mother	CMD-MR	Our report
	c.1251G>A	9	Gln417 =	Mother		c.1186G>A	8	Glu396*	Father	CMD-MR	Song et al. (1)
	c.1251G>A	9	Gln417 =	Mother		c.789+2T>G	–	–	Father	MEB	Song et al. (1)
	c.1251G>A	9	Gln417 =	Father		–	6-9del	–	Mother	CMD-MR	Song et al. (1)
	c.1251G > A	9	Gln417 =	Mother		c.789+2T>A	–	–	Father	WWS	Lin et al. (11)
	c.1251G>A	9	Gln417 =	Father		c.990del	7	IIe331Serfs*2	Mother	MEB	Song et al. (1)
	c.1354T>A	10	*452Arg	NA		c.1354T>A	10	*452Arg	NA	WWS	Willer et al. (12)
	c.1354T>A	10	*452Arg	NA		c.1315G>T	10	Glu439*	NA	CMD-MR	Meng et al. (16)
	c.1354T>G	10	*452Arg	NA		c.184del	1	Val62Serfs*29	NA	LGMD	Nallamilli et al. (8)
Group 2 (n=18)	c.184del	1	Val62Serfs*29	NA		c.790-1G>C	–	–	NA	WWS	Wojcik et al. (29)
	c.217G>T	1	Glu73*	Novel		c.217G>T	1	Glu73*	Novel	WWS	Bayram et al. (30)
	c.258-1G>A	–	–	NA		c.716-719del	1	Glu239Valfs*6	NA	WWS	Sframeli et al. (9)
	c258-1G>C	–	–	Novel		c.505A>T	2	Lys169*	Novel	LGMD	Park et al. (31)
	c.550C>T	3	Arg184*	NA		c.550C>T	3	Arg184*	NA	WWS	Alharbi et al. (24)
	c.627-628del	3	Arg209fs*3	NA		c.627-628del	3	Arg209fs*3	NA	CMD-MR	Marangoni et al. (14)
	c.643C>T	3	Gln215*	NA		–	9-10del	–	NA	WWS	Willer et al. (12)
	c.790-1G>C	–	–	NA		c.790-1G>C	–	–	NA	WWS	Alharbi et al. (24)
	c.832A>T	5	Lys278*	Mother		c.832A>T	5	Lys278*	Father	MEB	Roscioli et al. (3)
	c.836-?_1119+?dup	6-8	Val374Rfs*8	NA		c.836-?_1119+?dup	6-8	Val374Rfs*8	NA	LGMD	Cirak et al. (18)
	c.1120-1G>T	–	–	NA		c.1120-1G>T	–	–	NA	WWS	Willer et al. (12)
	c.1186G>T	9	Glu396*	Mother		c.1186G>T	9	Glu396*	Father	WWS	Roscioli et al. (3)
	–	3del(a)	–	NA		–	3del(a)	–	NA	WWS	Willer et al. (12)
	–	3-5del	–	NA		–	3-5del	–	NA	WWS	Roscioli et al. (3)
	–	6-8del	–	Mother		–	6-8del	–	Father	WWS	Roscioli et al. (3)
	–	6-9del	–	Mother		c.1114-1116del	8	Val373del	Father	LGMD	Yang et al. (21)
	–	9-10del	–	Mother		–	9-10del	–	Father	WWS	Roscioli et al. (3)
	–	2-10del	–	NA		–	2-10del	–	NA	WWS	Trkova et al. (32)

Group 1: 45 cases, each carrying at least one missense, synonymous, or in-frame variant. Group 2: 18 cases, with neither variant being missense, synonymous, or in-frame. *, stop codon; a: g., (16,401,191–16,406,273) (16,409,318–16,431,594)del. CMD, congenital muscular dystrophy; LGMD, limb-girdle muscular dystrophy; MEB, muscle-eye-brain disease; MR, mental retardation; NA, not available; WWS, Walker-Warburg syndrome.

Currently, there is no curative treatment for α-dystroglycanopathies. In our case, oral levetiracetam has been administered to manage epileptic seizures, but no effective therapies are available to address the motor and intellectual developmental impairments. Increasing ribitol levels may represent a potential therapeutic strategy for patients with CRPPA-related α-dystroglycanopathy (4). Further elucidation of CRPPA’s structural dynamics and substrate interaction mechanisms may accelerate targeted therapy development for this subset of α-dystroglycanopathies.

Conclusions

In summary, we identified two variants in the CRPPA gene, including the novel variant c.1119+2T>G. The patient exhibited clinical features consistent with CMD-MR, thereby expanding the phenotypic spectrum associated with α-dystroglycanopathies.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of Institutional Review Board of The Second Hospital of Shandong University (approval No. KYLL-2022D017) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.