A Case of Hereditary Spastic Paraplegia Type 50 With a Novel AP4M1 Variant and a Brief Review of the Literature

ABSTRACT

We report a case of hereditary spastic paraplegia type 50, an extremely rare disease characterized by upper motor neuron dysfunction. This case underscores the importance of considering genetic etiologies in patients previously diagnosed with cerebral palsy, especially when clinical history, presentation, and imaging findings are inconsistent with typical brain injury patterns.

1. Introduction

Hereditary spastic paraplegia (SPG) refers to a heterogeneous group of monogenic diseases characterized by upper motor neuron dysfunction and degeneration, leading to progressive spasticity of the lower limbs [1]. To date, more than 88 genes and 100 genetic loci have been implicated in SPG pathogenesis [1, 2].

AP4‐associated SPG results from biallelic loss‐of‐function variants in one of the four genes encoding the subunits of the adaptor protein complex 4 (AP4): AP4B1 (SPG type 47), AP4M1 (SPG type 50), AP4E1 (SPG type 51), and AP4S1 (SPG type 52) [1, 3]. The AP4 complex is ubiquitously expressed in human tissues, including the central nervous system. It is primarily localized to the trans‐Golgi network, where it mediates protein trafficking to other cellular compartments [1, 3]. Since the loss of any one subunit renders the entire complex nonfunctional, biallelic loss‐of‐function variants in any of these four genes result in the same pathophysiological defect and a clinically overlapping phenotype [1, 3].

Symptom onset typically occurs in infancy and includes global developmental delay, infantile hypotonia, postnatal microcephaly, and progressive lower‐limb spasticity, which may extend to the upper limbs, resulting in spastic tetraplegia [3, 4]. By the second decade of life, most affected individuals are wheelchair‐dependent and exhibit severe cognitive impairment [4]. Life expectancy is not yet well established, as the oldest reported individuals are young adults, but the disease is considered life‐limiting [3, 4].

SPG type 50 (OMIM #612936), caused by biallelic pathogenic variants in the AP4M1 gene (OMIM #602296), is an extremely rare condition, with fewer than 100 reported cases [4]. The first cases were described in 2009 [5]. Here, we present the case of a Venezuelan patient who was misdiagnosed with cerebral palsy for several years. We also briefly review previously reported cases of SPG type 50, highlighting common features and prevalent manifestations of the disease.

2. Case History/Examination

We present the case of an 18‐year‐old woman from Venezuela. Both parents originate from the same geographic region of this country, with no known history of consanguinity (Figure 1). The pregnancy was monitored and uneventful. She was born at term via spontaneous vaginal delivery, with a birth weight of 3100 g (−0.3 SD), a length of 54 cm (+2.6 SD), and an undocumented head circumference. The Apgar score was not recorded. Neonatal asphyxia was suspected due to a nuchal cord, requiring neonatal resuscitation, followed by complete recovery within the first day of life. She was discharged on the second day, with no neonatal seizures or evidence of neonatal encephalopathy.

FIGURE 1.

Pedigree showing the segregation of the AP4M1 variants. WT = wild type; the black symbol indicates the affected patient.

The patient experienced her first generalized tonic–clonic seizure at 7 months of age in the context of post‐vaccination fever. By the age of 4, she had experienced six episodes of simple febrile seizures. Her psychomotor development was globally delayed, though with no signs of regression. She began walking at approximately 3 years of age, albeit with persistent difficulty and a progressive pattern of spastic tetraparesis predominantly affecting the lower limbs. An unspecified foot deformity was identified and required orthopedic surgery. Additional findings included postnatal microcephaly, severe language impairment, left‐sided convergent strabismus, and high myopia.

3. Differential Diagnosis, Investigations and Treatment

Initially, a preliminary diagnosis of cerebral palsy attributed to neonatal asphyxia was considered. The patient has been living in Portugal since the age of 11 and was first evaluated in the Pediatric Neurology Consultation at 12 years of age, after a new episode of seizure, which led to a diagnosis of epilepsy. At that time, she measured 140 cm in height (−2.2 SD) and had a head circumference of 50 cm (−2.7 SD). Neurological examination revealed generalized hypertonia, brisk and polykinetic deep tendon reflexes in all four limbs (especially the lower limbs), indifferent plantar reflexes, and diminished but present facial expression without drooling, tremor, or nystagmus. Oculomotricity was intact, except for left‐sided convergent strabismus. Gait required adult support and displayed a pattern of spastic tetraparesis predominantly in the lower limbs.

Treatment was initiated with carbamazepine 200 mg/day (5 mg/kg) and baclofen 25 mg/day (0.7 mg/kg). Electroencephalogram showed no epileptiform discharges. Brain magnetic resonance imaging (MRI) demonstrated partial atrophy/hypoplasia of the posterior third of the corpus callosum, with significant thinning and volume reduction of the splenium. The gyri in the posterior third of the corpus callosum exhibited a verticalized pattern. Additional findings included small, slightly irregular bilateral gyri in the inner hemispheres and cortical convexity, suggestive of cortical dysplasia. Asymmetric lateral ventricles were also noted, with right‐sided dominance (Figure 2).

FIGURE 2.

Brain MRI features. (A) Axial T2‐FLAIR MRI shows lateral ventricles asymmetry, with right‐sided dominance (black arrow). (B) Sagittal fat suppressed spoiled gradient (FS SPGR) T1 image displays partial atrophy/hypoplasia of the posterior third of the corpus callosum, with thinning and volume reduction of the splenium (white arrow). The gyri in the posterior third of the corpus callosum exhibited a verticalized pattern (*).

Given these MRI findings, which suggested a cerebral palsy‐like phenotype of possible genetic origin, the patient was referred to the Medical Genetics Consultation. Dysmorphology assessment identified slender fingers, truncal shortening, facial hypotonia, and minor dysmorphic facial features, including a broad nasal ridge and a bulbous nose (Figure 3).

FIGURE 3.

Facial appearance of the patient at 18 years of age, showing a broad nasal ridge and a bulbous nose. Photograph shared with parental consent.

Molecular testing for fragile X syndrome was negative. Microarray‐based comparative genomic hybridization analysis (Array‐CGH, 180 K platform, Signature Genomics, PerkinElmer) revealed no pathogenic copy number variations. Whole exome sequencing (WES) (CentoXome Solo targeted nucleotides covered ≥ 20X 99.66%, Centogene, Rostock, Germany) identified two heterozygous variants in the AP4M1 gene (NM_004722.4): c.1137+1G>T p.(?) and c.1360T>C, p.*454Argext*84.

The first variant, c.1137+1G>T p.(?), has an allele frequency of 0.000009922 (16/1612556 alleles) in GnomAD v4.1.0, with no homozygous occurrence, and four entries in ClinVar (three classified as pathogenic and one as likely pathogenic), and it was reported in three articles in the literature [5, 6, 7]. It is predicted to disrupt a highly conserved donor splice site. The computational scores (BayesDel (addAF and noAF)) suggest a pathogenic effect, as well as the in silico tools (dbscSNV1_ADA, dbscSNV1_RF, SpliceAI score, DS_DL_spliceai), and the CADD score is 33.

The second variant, c.1360T>C, p.*454Argext*84, which results in the loss of a stop codon, has an allele frequency of 0.0000080627 (13/1,612,354 alleles) in GnomAD v4.1.0, with no homozygous occurrence, has two entries in ClinVar (classified as a variant of unknown significance), and was not reported in the literature. Most computational scores (BayesDel_addAF, Eigen, Eigen_PC, FATHMM_MKL) suggest a pathogenic effect, and the CADD score is 19.06.

The first variant was classified as pathogenic, while the second was initially considered a variant of uncertain clinical significance. Parental segregation analysis demonstrated the variants were in trans, establishing compound heterozygosity in the patient. Consequently, the second variant was reclassified as likely pathogenic, confirming the diagnosis of SPG type 50.

4. Outcome and Follow‐Up

Currently, the patient is 18 years old, with a height of 155 cm (−1.2 SD) and a head circumference of 52.7 cm (−1.3 SD). She requires assisted ambulation with a wheelchair due to spastic tetraparesis, predominantly affecting the lower limbs. She has severe intellectual disability with profound language impairment, characterized by poor, repetitive, monosyllabic speech. She lacks sphincter control. Epilepsy is well controlled with carbamazepine monotherapy (200 mg/day), and she has been seizure‐free for the past two years. She also maintains baclofen therapy (25 mg/day) for spasticity management.

The patient receives multidisciplinary care, including follow‐up in Physical and Rehabilitation Medicine, Stomatology, Ophthalmology, Otorhinolaryngology, and Gynecology. Transition to Adult Neurology Consultation is currently underway. She attends an educational institution suited to her needs and benefits from available social support. Her parents have received genetic counseling and expressed interest in prenatal diagnosis for future pregnancies.

5. Discussion

Our patient exhibits clinical features consistent with previously reported cases of SPG type 50. Table 1 summarizes the characteristics of 25 patients from 14 families, including our patient [5, 8, 9, 10, 11, 12, 13, 14, 15, 16].

TABLE 1.

Clinical features of patients with SPG type 50 in this and previous reports.

	Present patient	Verkerk et al. [5]	Tüysüz et al. [8]	Jameel et al. [9]	Bettencourt et al. [10]	Duerinckx et al. [11]	Roubertie et al. [12]	Hebbar et al. [13]	Jezela‐Starek et al. [14]	Mercan et al. [15]	Becker et al. [16]	Total
Number of families	1	1	2	1	1	1	1	1	1	1	3	14
Number of patients	1	5	4	2	3	1	3	1	1	1	3	25
Families origin	Venezuelan	Moroccan	Turkish	Pakistani	Greek	Turkish	Moroccan	NA	NA	NA	2/3 Turkish 1/3 Arab
Consanguinity	−	+	+	+	−	+	+	+	NA	+	+	11/14
Sex	F	3 M/2F	3F/1M	M	2 M/1F	M	F	F	M	F	2F/1M	14F/11M
Age (years)	18	1.5–24	2.5–17	12–14	NA	8	16–25	6	8.5	NA	3–8
Genetic variants	HTZ c.1137 + 1G>T c.1360 T>C	HMZ c.1137 + 1G>T	HMZ 2/4 c.1012C>T 2/4 c.952C>T	HMZ c.194_195delAT	HTZ c.521dupT/c.955 T>C	HMZ c.1170C>T	HMZ c.916C>T	HMZ c.1026–1G>T	HTZ c.566del/ c.916C>T	HMZ c.952C>T	HMZ c.1012C>T
Intellectual disability	Severe	Severe	Moderate–severe	Severe	Severe	Severe	Moderate–severe	Severe	Severe	NA	Moderate–severe	24/25
Speech disorder	+	+	+	+	+	+	+	+	+	NA	+	24/25
Infantile hypotonia	NA	+	1/4, 3/4 NA	+	NA	+	NA	+	+	+	1/3	13/25
Spasticity	+	4/5, 1/5 NA	+	+	+	+	+	+	+	+	+	24/25
Ambulation	Assisted	−	−	−	Assisted	Assisted	2/3 (Assisted)	NA	NA	NA	2/3 (Assisted)	9/25 (Assisted)
Seizures	+	NA	+	1/2	+	+	2/3	+	+	+	+	18/25
Microcephaly	+ (−2.7 SD)	1/5, 1/5 NA (−2.5 SD)	2/4 (−3 to −4 SD)	−	NA	+ (−4.7 SD)	1/3 (−4.2 SD)	+ (−3 SD)	+	+	+ (−2.5 to −4.4SD)	12/25
Facial dysmorphisms	+	NA	+	1/2	+	−	+	NA	NA	NA	1/3	13/25
Feet deformity	+	2/5	1/4	−	NA	+	+	NA	+	NA	1/3	10/25
Short stature	−	NA	NA	NA	NA	+	2/3	NA	−	NA	NA	3/25
Sphincter control	−	−	1/4	NA	NA	NA	NA	−	NA	NA	NA	1/25
Ventriculomegaly/asymmetry	+	3/5, 2/5 NA	+	1/2	−	+	+	+	NA	+	2/3	17/25
Thin splenium of CC	+	3/5, 2/5 NA	+	1/2	+	+	NA	+	NA	NA	+	17/25
White matter loss	−	3/5, 2/5 NA	2/4	NA	−	−	+	NA	NA	NA	1/3	9/25
Cerebral atrophy	−	NA	1/4	NA	−	+	+	NA	NA	NA	2/3	7/25
Cerebellar atrophy	−	2/5, 2/5 NA	−	1/2	+	−	NA	NA	NA	NA	−	6/25

Abbreviations: −, absent; +, present; CC, corpus callosum; F, female; HMZ, homozigoty; HTZ, compound heterozigoty; M, male; NA, no data available; SD, standard deviation.

Consanguinity was noted in 11/14 families, with most patients originating from regions where consanguinity is prevalent. To our knowledge, this is the first reported case involving a Latin American family, specifically from Venezuela.

Intellectual disability (usually severe), language impairment, and spasticity were present in all cases with available data. Gait abnormalities were evident, with 13/25 patients unable to walk and 9/25 requiring assisted walking (data not available for 3/25). Infantile hypotonia was reported in 13/25 patients (absent in 2/25; data unavailable in 10/25, including our patient).

Seizures or epilepsy occurred in 18/25 patients, often beginning in the first two years of life, either unprovoked or associated with fever. Seizure types included both focal and generalized seizures (tonic–clonic, tonic, or myoclonic). Prognosis is generally favorable, with good control on monotherapy [3, 6].

Microcephaly was noted in approximately half the cases (12/25), ranging from −2.5 to −4.7 SD. Dysmorphic facial features were present in 13/25 patients, including a broad nasal bridge, a bulbous nose, a wide mouth, a short philtrum, downturned mouth corners, an everted upper vermilion, and bitemporal narrowing. However, a consistent dysmorphic pattern has not been established [6].

Foot deformities, particularly pes equinovarus, were reported in 10/25 cases. Some studies also report short stature (3/25), though this information is generally unavailable for most cases.

Characteristic brain MRI findings included asymmetric ventricles or asymmetric ventriculomegaly (17/25), thin splenium of the corpus callosum (17/25), white matter loss (9/25), cerebral atrophy (7/25), and cerebellar atrophy (6/25). Less consistently reported findings included vessel tortuosity [5], flat/thin hippocampus [8], brain iron overload [12], delayed white matter myelination, and peri‐hypothalamic atrophy [15].

Although detailed discussion is beyond the scope of this publication, we emphasize that other AP4‐associated SPG subtypes exhibit a similar phenotype. Thus, the combination of infantile hypotonia, minor facial dysmorphisms, microcephaly, spastic paraplegia or tetraplegia, intellectual disability, and typical MRI findings should raise suspicion for AP4‐associated SPG [3, 6]. Also, the clinical phenotype overlaps with other hereditary spastic paraplegias and with cerebral palsies [17]. To our knowledge, no genotype–phenotype correlations have been reported for any of the four genes known to cause AP4‐associated SPG [3].

This case illustrates the importance of considering genetic etiologies in patients previously labeled as having cerebral palsy when the clinical history, presentation, and imaging findings do not align with typical brain injury patterns [18]. ‘Red flags’ include consanguinity, unremarkable perinatal history, syndromic features, progressive neurological symptoms, movement disorders, global developmental delay or intellectual disability, corpus callosum abnormalities, cerebellar atrophy, and a normal brain MRI. In particular, the co‐occurrence of multiple ‘red flags’ may strongly suggest the need for genetic investigation, as individually many features are non‐specific [18].

Beyond the importance of genetic diagnosis for better medical follow‐up and genetic counseling, therapeutic options for SPG type 50 may be available in the near future, with the emergence and advances in gene therapy. Recently, a single‐patient phase 1 trial was conducted in the United States (NCT06069687), involving a 4‐year‐old patient with SPG type 50 (variants AP4M1 c.916C>T and c.696dupG) [4]. An adeno‐associated virus vector carrying the functional AP4M1 gene was administered intrathecally. As SPG type 50 results from loss of expression/function mutations, gene re‐expression was anticipated to be effective. Preliminary data suggest stabilization of disease progression with only minor adverse effects [4]. A larger phase 1/2 clinical trial (NCT05518188), targeting children aged 4 months to 10 years, is currently recruiting participants, and no results have been published yet.

To the best of our knowledge, this is the first reported case of SPG type 50 in a Venezuelan family. We also report, for the first time, the AP4M1 variant c.1360 T>C, p.*454Argext*84, initially classified as a variant of uncertain significance and later reclassified as likely pathogenic based on segregation analysis. The patient displays clinical and imaging features highly consistent with previously described cases, contributing to a better understanding of the SPG type 50 phenotype.

Author Contributions

Ana Teresa Guerra: conceptualization, writing – original draft, writing – review and editing. André M. Travessa: conceptualization, writing – original draft, writing – review and editing. José Paulo Monteiro: conceptualization, supervision, writing – review and editing.

Ethics Statement

Ethical approval is not required for this study (case report) in accordance with national guidelines. Written informed consent was obtained from the father of the patient for publication of the medical details and accompanying images/video. The father is permitted to provide consent on behalf of the patient.

Consent

Written informed consent was obtained from the father of the patient for publication of the medical details and accompanying images/video. The father is permitted to provide consent on behalf of the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Guerra A. T., Travessa A. M., and Monteiro J. P., “A Case of Hereditary Spastic Paraplegia Type 50 With a Novel AP4M1 Variant and a Brief Review of the Literature,” Clinical Case Reports 13, no. 10 (2025): e70954, 10.1002/ccr3.70954.

Data Availability Statement

Data supporting the findings of this case report are available in this article, and further inquiries can be directed to the corresponding author.