Abstract
Proximal muscle weakness is a recognized feature of hypophosphatasia (HPP), although significant structural muscle pathology is not typically observed. We report a 48-year-old woman with a 20-year history of progressive gait disturbance, proximal muscle weakness (Medical Research Council grade 2-4), and recurrent low-trauma fractures. Laboratory evaluation revealed persistently low serum alkaline phosphatase, and genetic testing identified a heterozygous likely pathogenic variant in ALPL (NM_000478.6:c.1559del; p.[Leu520Argfs*86]), confirming the diagnosis of HPP. However, severe muscle weakness and extensive fatty infiltration on muscle magnetic resonance imaging were disproportionate to what would be expected from HPP alone, prompting further evaluation. Additional genetic analysis identified a previously unreported homozygous intronic deletion in COL6A2 (NM_001849.4:c.1771-18_1771-3del), classified as likely pathogenic and predicted to affect splicing with uncertain protein consequences, confirming concurrent collagen VI–related muscular dystrophy (COL6-RD). Family genetic testing identified the same ALPL variant in the proband's 16-year-old daughter, who was subsequently diagnosed with HPP and found to be a carrier of COL6-RD. This case highlights that HPP and muscular dystrophy can coexist and underscores the importance of comprehensive neuromuscular evaluation when muscle weakness is present in patients with HPP.
Keywords: hypophosphatasia, collagen VI–related muscular dystrophy, gait disturbance, muscle MRI, muscle ultrasonography
Introduction
Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function variants in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP) [1]. It is characterized by a broad clinical spectrum, with hallmark features including skeletal hypomineralization, recurrent fractures, chronic musculoskeletal pain, and premature loss of early teeth [1]. In addition, neuromuscular symptoms such as muscle weakness and waddling gait have been reported in HPP, though the precise pathophysiological mechanisms remain incompletely understood [2, 3].
Muscle weakness in HPP has been described as mild proximal muscle weakness predominantly involving the lower extremities, associated with waddling gait and stair-climbing difficulty [4, 5]. However, significant structural muscle pathology is not considered characteristic of HPP [2, 5, 6]. Therefore, severe weakness in patients with HPP should prompt evaluation for a coexisting neuromuscular disorder.
We report a 48-year-old woman with confirmed HPP who presented with severe progressive proximal muscle weakness and recurrent fractures in whom further evaluation revealed concurrent collagen VI–related muscular dystrophy (COL6-RD). This case highlights the importance of thorough neuromuscular evaluation, including electrodiagnostic studies and muscle imaging, in patients with HPP presenting with muscle weakness.
Case presentation
A 48-year-old premenopausal woman was referred to the Department of Physical Medicine and Rehabilitation and the Department of Endocrinology and Metabolism for evaluation of progressive gait disturbance. She reported a 20-year history of slowly progressive bilateral lower extremity weakness, with onset in her mid-twenties. Initially, she had difficulty rising from the floor without hand support; by her early forties, she became unable to rise from the chair without upper extremity assistance and required bilateral single canes during level walking.
Her past medical history was notable for difficulty running since childhood. She also experienced recurrent ankle sprains during running activities. She underwent surgical procedures on both Achilles tendons at approximately age 9 (right) and age 14 (left), although the exact diagnoses were not recalled. At age 32, she experienced early loss of 2 permanent teeth without an identifiable cause, requiring dental implant placement. Although she had no history of fractures during childhood or adolescence, she sustained multiple low-energy fractures in her forties, including fractures of the patella, ribs, fibula, and coccyx (Table 1). She denied any family history of gait disturbance or neuromuscular disease, but her mother had osteoporosis.
Table 1.
Summary of clinical characteristics
| Variable | Case 1 (proband) | Case 2 (daughter) |
|---|---|---|
| Age | 48 years | 16 years |
| Sex | Female | Female |
| Clinical presentations | Fractures and muscle weakness | Fractures |
| Fractures | Patella, ribs, fibula, coccyx | Wrist, ankle |
| Dental findings | Yes (early loss of 2 permanent teeth at age 32) | None |
| Muscle strength (MRC scale) | Symmetric proximal girdle weakness (MRC grade 2-4) | Normal (MRC grade 5) |
| Serum total ALPa | 0.42 μkat/L (25 U/L) | 0.60 μkat/L (36 U/L) |
| Serum PLPb | 935 nmol/L (231 μg/L) | 243 nmol/L (60 μg/L) |
| BMD by DXA | Lumbar spine: 1.089 g/cm2 (T-score: −0.5; Z-score: −0.2) | Lumbar spine: 1.093 g/cm2 (Z-score: 0.1) |
| Total femur: 0.598 g/cm2 (T-score: −3.1; Z-score −3.1) | ||
| COL6-RD phenotypic features | Keloid scar (right hand dorsum); keratosis pilaris; contractures of shoulder, ankle, and finger DIP joints; paradoxical PIP joint hyperlaxity | None |
| 6-minute walk test | NA | 422 m (62.74% of normal range) |
| Diagnosis | HPP and COL6-RD | HPP and carrier of COL6-RD variant |
| Treatment | Calcium + Vitamin D supplementation | Calcium + vitamin D supplementation; efzimfotase alfa clinical trial |
Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; COL6-RD, collagen VI-related muscular dystrophy; DIP, distal interphalangeal; DXA, dual energy X-ray absorptiometry; HPP, hypophosphatasia; MRC, Medical Research Council; NA, not available (not tested); PIP, proximal interphalangeal; PLP, pyridoxal-5-phosphate.
a Serum total ALP was converted to International System (SI) units using the online calculator at https://academic.oup.com/amamanualofstyle/si-conversion-calculator. Normal range for adult 0.58-1.74 μkat/L [35-104 U/L]; normal range for adolescents 1.00-5.01 μkat/L [60-300 U/L]).
b Normal range 20-202 nmol/L (5-50 μg/L)
Diagnostic assessment
Physical examination revealed symmetric proximal girdle muscle weakness, graded 2-4/5 on the Medical Research Council (MRC) scale (shoulder forward flexion 2/5, elbow flexion and extension 4/5, hip flexion 3/5, knee extension 3/5). Gait assessment demonstrated a waddling pattern, with excessive lumbar lordosis noted on standing. Sensory examination was intact in all modalities. Bilateral ankle plantar flexion contractures of 20° were noted. Passive shoulder range of motion was restricted bilaterally, with forward flexion limited to 90° and internal rotation to 40°.
Laboratory investigations revealed persistently low serum total alkaline phosphatase (ALP), 0.42 μkat/L (25 U/L) (normal range 0.58-1.74 μkat/L [35-104 U/L]), with increased serum pyridoxal-5-phosphate 935 nmol/L (231 μg/L) (normal range 20-202 nmol/L [5-50 μg/L]) (Table 1). Serum total calcium was 2.38 mmol/L (9.5 mg/dL) (normal range 2.15-2.55 mmol/L [8.6-10.2 mg/dL]) and phosphorus was 1.45 mmol/L (4.5 mg/dL) (normal range 0.81-1.45 mmol/L [2.5-4.5 mg/dL]). Decreased serum 25-hydroxyvitamin D level of 34.94 nmol/L (14.0 ng/mL) (normal range 49.92-124.80 nmol/L [20-50 ng/mL]) and increased intact parathyroid hormone level of 97.30 ng/L (97.3 pg/mL) (normal range 17.3-74.1 ng/L [17.3-74.1 pg/mL]) were observed. Serum creatine kinase (CK) was mildly elevated at 4.63 μkat/L (277 IU/L) (normal range 2.25-3.57 μkat/L [135-214 IU/L]).
99mTechnetium bone scintigraphy revealed focal increased uptake in the posterior arc of the left fifth and sixth ribs and the left ankle/tarsal bones (Fig. 1A and 1B), and subsequent magnetic resonance imaging (MRI) confirmed talocrural joint arthritis and bone marrow edema at the calcaneocuboid joint (Fig. 1C and 1D), whereas plain radiographs showed no metatarsal fractures (Fig. 1E and 1F).
Figure 1.
Skeletal imaging findings. (A, B) 99mTechnetium bone scintigraphy in anterior (A) and posterior (B) views demonstrates focal increased radiotracer uptake in the posterior arc of the left 5th and 6th ribs (arrowheads), suggestive of fractures, and in the left ankle and tarsal bones (arrows), indicating possible joint pathology or occult fractures. (C, D) Sagittal T2-weighted fat-suppressed and T1-weighted magnetic resonance imaging of the left ankle shows arthritis of the talocrural joint (arrowheads) and bone marrow edema in the superior aspect of the calcaneocuboid joint (arrows), corresponding to the areas of increased uptake observed on bone scintigraphy. (E, F) Plain radiographs of both feet show no definite evidence of metatarsal fractures.
Nerve conduction studies demonstrated normal sensory and motor conduction parameters in both the upper and lower extremities. Needle electromyography revealed no abnormal spontaneous activity in the sampled muscles; however, motor unit action potential analysis demonstrated myopathic morphology with early recruitment in proximal girdle muscles (Table 2). Muscle ultrasonography revealed Heckmatt scale grade 4 echogenicity changes in the proximal girdle muscles, indicative of severe fatty degeneration (Fig. 2) [7].
Table 2.
Needle electromyography findings
| Muscle (left side) | Abnormal spontaneous activity | MUAP analysis | ||
|---|---|---|---|---|
| Fibrillation potential | Positive sharp wave | MUAP morphology | MUAP recruitment pattern | |
| Deltoid | None | None | Short polyphasic | Early |
| Biceps brachii | None | None | Short polyphasic | Early |
| Flexor carpi radialis | None | None | Short polyphasic | Early |
| First dorsal interosseous | None | None | Normal | Normal |
| Vastus medialis | None | None | Short polyphasic | Early |
| Rectus femoris | None | None | Short polyphasic | Early |
| Gastrocnemius (medial head) | None | None | NA | Nil |
| Tibialis anterior | None | None | Short polyphasic | Early |
| Lower cervical paraspinalis | None | None | NA | NA |
| Middle lumbar paraspinalis | None | None | NA | NA |
| Lower lumbar paraspinalis | None | None | NA | NA |
Abbreviations: MUAP, motor unit action potential; NA, not available (not tested).
Figure 2.
Muscle ultrasonography findings. (A, C) Muscle ultrasonography demonstrates Heckmatt grade 4 changes in the (A) left rectus femoris (arrow) and (C) left biceps brachii (arrow), with markedly increased echogenicity, complete loss of normal muscle architecture, and obscuration of the underlying bone shadow. (B, D) Normal muscle ultrasonography of the (B) left rectus femoris and (D) left biceps brachii for comparison, showing preserved muscle architecture (arrow) and a clear bone cortical margin (arrowhead).
Given the clinical findings of recurrent low-trauma fractures, early permanent tooth loss, and persistently low serum ALP, HPP was initially suspected as the underlying cause of gait disturbance. Targeted panel sequencing, designed to diagnose muscular dystrophy and myopathy and including ALPL, identified a heterozygous likely pathogenic variant (NM_000478.6:c.1559del, predicted p.(Leu520Argfs*86) (Fig. 3A and 3B), confirming the diagnosis of HPP.
Figure 3.
Genetic findings from targeted panel sequencing. (A) Integrative Genomics Viewer (IGV) snapshot from the proband showing the heterozygous ALPL frameshift variant (NM_000478.6:c.1559del, p.[Leu520Argfs*86]). (B) Sequence chromatograms from the proband and her daughter and son confirming the ALPL variant. (C) IGV snapshot from the proband showing homozygous COL6A2 intronic deletion (NM_001849.4:c.1771-18_1771-3del, p.?). (D) Sequence chromatograms from the family demonstrating the COL6A2 variant.
The heterozygous ALPL c.1559del variant has been associated with variable clinical phenotypes ranging from asymptomatic carriers to symptomatic childhood or adult HPP phenotypes [8-11]. However, severe muscle weakness and extensive fatty muscle degeneration on ultrasonography in the present case were judged disproportionate to what could be attributed to HPP alone, raising suspicion for a concurrent muscular dystrophy. Lower extremity MRI was performed to assess structural muscle pathology. MRI demonstrated an “outside-in” fatty infiltration pattern in the vastus lateralis and a “central shadow” pattern in the rectus femoris (Fig. 4), both characteristic imaging signatures of COL6-RD [12]. Re-examination identified additional phenotypic features consistent with COL6-RD: a keloid scar, keratosis pilaris, contracture of the distal interphalangeal (DIP) joints of the fingers, and paradoxical hyperlaxity of the proximal interphalangeal (PIP) joints (Table 1). Subsequent genetic testing of the COL6A2 gene revealed a homozygous intronic deletion, NM_001849.4:c.1771-18_1771-3del, not previously reported and predicted to disrupt splicing (Fig. 3C and 3D), confirming the concurrent diagnosis of COL6-RD.
Figure 4.
Lower extremity magnetic resonance imaging (MRI) findings. (A) T1-weighted axial MRI of the bilateral thigh muscles demonstrate severe fatty infiltration with centrally predominant involvement of the rectus femoris (“central shadow” pattern; arrows) and peripherally predominant involvement of the vastus lateralis (“outside-in” pattern; arrowheads), consistent with the characteristic imaging pattern of collagen VI–related muscular dystrophy. (B) T1-weighted axial MRI from a normal subject for comparison shows preserved muscle architecture of the rectus femoris (arrow) and vastus lateralis (arrowheads) without fatty infiltration.
Genetic testing was extended to the proband's son (aged 20 years) and daughter (aged 16 years). Both were found to carry a heterozygous COL6A2 c.1771-18_1771-3del variant, without clinical manifestations (Fig. 3). The heterozygous ALPL c.1559del variant was additionally identified in the 16-year-old daughter (Case 2) (Table 1). She reported a history of a wrist fracture at age 12 years and an ankle fracture at age 13 years, with otherwise normal development and menarche at age 12 years. Neuromuscular examination revealed normal muscle strength of both upper and lower limbs. Serum total ALP was low 0.60 μkat/L (36 U/L) (normal range for adolescents 1.00-5.01 μkat/L [60-300 U/L]), whereas bone mineral density was within the normal range for age (Table 1). These findings established a diagnosis of HPP in the daughter (Case 2) (Fig. 3). Genetic testing of the proband's parents was not performed, and there was no known parental consanguinity.
Treatment
Self-stretching exercises were recommended for the proband (Case 1) to prevent progression of joint contractures associated with COL6-RD. Both cases were referred to the Department of Endocrinology and Metabolism for further management. The proband (Case 1) received calcium carbonate 250 mg and cholecalciferol 1000 units daily for supportive management of vitamin D deficiency and secondary hyperparathyroidism. Her daughter (Case 2) received the same supplementation and was additionally enrolled in a clinical trial of efzimfotase alfa, an investigational enzyme replacement therapy for HPP.
Outcome and follow-up
In the proband (Case 1), serum 25-hydroxyvitamin D levels improved to 69.39 nmol/L (27.8 ng/mL), and intact parathyroid hormone levels normalized to 35.20 ng/L (35.2 pg/mL). However, proximal muscle weakness persisted with no improvement in MRC grade.
Discussion
This case highlights the incidental coexistence of HPP and COL6-RD in a patient with progressive proximal muscle weakness and recurrent fractures. Although the patient's history of recurrent low-trauma fractures and persistently low serum ALP initially suggested HPP as the primary cause of gait disturbance, the severity of muscle weakness and the pattern of fatty infiltration on lower extremity MRI led to the identification of a coexisting muscular dystrophy. This case underscores the importance of considering a secondary diagnosis when severe weakness and fatty degeneration are present in patients with HPP.
HPP is a rare inherited metabolic disorder caused by loss-of-function variants in the ALPL gene, resulting in deficient TNSALP activity [1]. Although skeletal and dental manifestations are the most recognized features of HPP, neuromuscular symptoms such as waddling gait and muscle weakness are also reported [1, 6]. TNSALP deficiency may contribute to muscle weakness through impaired vitamin B6 metabolism, characterized by accumulation of pyridoxal-5′-phosphate in the circulation but reduced intracellular availability in muscle cells [2]. Additional mechanisms may include impaired glycogen phosphorylase activity leading to reduced muscle energy metabolism and mitochondrial dysfunction affecting adenosine triphosphate production [2].
Previous reports have described muscle weakness in HPP as generally mild (MRC grade 4/5), predominantly affecting the proximal lower extremities and presenting with waddling gait and difficulty climbing stairs [4, 5]. These clinical manifestations may resemble muscular dystrophy. Electromyography may demonstrate myopathic changes despite the absence of histological alterations, and serum CK levels typically remain normal or only mildly elevated in HPP [4, 5]. To our knowledge, reports describing muscle imaging findings in HPP are scarce. However, previous studies demonstrated either normal muscle fiber architecture or only minimal abnormalities on muscle biopsy [4, 5, 13], suggesting that marked structural muscle degeneration is not a typical feature of HPP. These findings may help differentiate HPP-associated muscle weakness from muscular dystrophy.
In the present case, severe proximal weakness (MRC grade 2-4) and extensive fatty degeneration on MRI raised suspicion for an additional structural myopathy. This interpretation was further supported by the absence of muscle weakness in the proband's daughter, who carried the same heterozygous ALPL variant. Muscle MRI revealed a characteristic findings of COL6-RD, including predominant fatty infiltration of the rectus femoris around the central tendon (“central shadow” pattern) and peripheral involvement of the vastus lateralis around the muscle fascia (“outside-in” pattern) [12]. These imaging findings guided further genetic evaluation and led to the identification of concurrent COL6-RD.
COL6-RD is caused by variants in COL6A1, COL6A2, or COL6A3, leading to extracellular matrix dysfunction and progressive fibro-fatty replacement of muscle [14, 15]. Because collagen VI is also expressed in skin and connective tissues, patients often exhibit extramuscular manifestations [14, 15]. Re-examination after recognition of the characteristic MRI pattern identified previously overlooked findings consistent with COL6-RD, including keloid scarring, keratosis pilaris, multiple joint contractures (shoulders, ankles, and finger DIP joints), and paradoxical finger PIP joint hyperlaxity.
To our knowledge, there is no known pathophysiological association between HPP and COL6-RD, and their coexistence in the present case is considered an exceptionally uncommon incidental finding. However, because HPP itself may present with proximal muscle weakness and waddling gait, the diagnosis of HPP may delay recognition of a coexisting myopathy. Therefore, severe weakness (particularly MRC grade ≤3) in patients with HPP should prompt careful evaluation for an additional neuromuscular disorder, including electrodiagnostic studies and muscle imaging.
Learning points
Two rare genetic disorders can coexist in a single patient; the primary diagnosis should not preclude evaluation for additional conditions.
In hypophosphatasia (HPP), disproportionately severe muscle weakness (MRC grade ≤3) should prompt evaluation for a coexisting neuromuscular disorder.
Muscle MRI can help distinguish HPP-related muscle weakness from structural myopathy.
Confirmation of a rare inherited disorder in a proband should prompt family-based genetic testing to detect additional affected individuals with subclinical disease.
Acknowledgments
The authors thank the patient and her family for consenting to the publication of this case report. We also thank Youn-Ji Hong for genetic diagnosis and analysis and Umi Lee for assistance with the acquisition of muscle ultrasound findings.
Abbreviations
- ALP
alkaline phosphatase
- CK
creatine kinase
- COL6-RD
collagen VI–related muscular dystrophy
- DIP
distal interphalangeal (joint)
- HPP
hypophosphatasia
- MRC
Medical Research Council
- MRI
magnetic resonance imaging
- PIP
proximal interphalangeal (joint)
- TNSALP
tissue-nonspecific alkaline phosphatase
Contributor Information
Yu Jin Im, Department of Physical Medicine and Rehabilitation, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
Young Bae Sohn, Department of Medical Genetics, Ajou University Medical Center, Ajou University School of Medicine, Suwon 16499, South Korea.
Yong Jun Choi, Department of Endocrinology and Metabolism, Ajou University Medical Center, Ajou University School of Medicine, Suwon 16499, South Korea.
Mi-Ae Jang, Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
Duk Hyun Sung, Department of Physical Medicine and Rehabilitation, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea.
Yoon-Sok Chung, Department of Endocrinology and Metabolism, Ajou University Medical Center, Ajou University School of Medicine, Suwon 16499, South Korea.
Contributors
All authors made individual contributions to authorship. Y.J.I., Y.J.C., and Y-S.C. were involved in the diagnosis and management of the patient. D.H.S. contributed to the musculoskeletal imaging evaluation and interpretation. Y.B.S. and M-A.J. contributed to genetic diagnosis and interpretation, and M-A.J. prepared the figure depicting the genetic findings. Y.J.I. drafted the manuscript. Y.B.S., Y.J.C., M-A.J., D.H.S., and Y-S.C. critically revised the manuscript. All authors reviewed and approved the final manuscript and agreed to be accountable for all aspects of the work.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed patient consent for publication
Signed informed consent obtained directly from the adult patient. Consent for publication of information regarding her minor daughter was also provided by the adult patient in her role as the child's legal guardian.
Data availability
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.