Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux–Lamy syndrome (OMIM #253200), is a rare lysosomal storage disorder caused by deficient activity of
In this study, we report a case of MPS VI with a novel variant in a Korean patient.
A Korean female aged 5 years and 8 months, who is the only child of a healthy, non-consanguineous Korean couple, visited our hospital because of her severe short stature (-2.66 of height z-score). Her developmental milestones and intelligence level were normal. She had a medical history of umbilical hernia and recurrent otitis media. Her parents complained about her snoring, mouth breathing, and intermittent sleep apnea. Subtle dysmorphic features, such as mild coarse face, joint contracture, hepatomegaly (one finger breadths), and limited range of joint motion, were observed. Radiographic images showed deformities, which was suggestive of skeletal dysplasia include the following: metaphyseal fraying and widening of multiple bones; short, broad, irregular shaped metacarpal and metatarsal bones; genu valgum; deformed configurations in distal radius and ulna; poorly developed acetabulum and femoral head deformity; and malformation of thoracolumbar vertebral body (Fig. 1A-F). Growth hormone (GH) provocation tests revealed a complete GH deficiency. Initially, targeted exome sequencing (TES) was performed because skeletal abnormalities, such as MPS, were suspected, and the result revealed a compound heterozygous mutation of the
This case report discusses the fourth MPS VI patient in Korea, wherein a novel variant was identified in the patient. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the
This variant was neither found in ExAC nor 1000G databases. The p.Ser386 residue is completely conserved across multiple species and is close to the glycosylation site (location 366). Another variant, c.512G>A (p.Gly171Asp), identified in the patient, was previously reported in the case of P3 (Table 2) with homozygote allele carriers who presented with short stature, coarse face, corneal opacity, and stiffness in multiple joints.
Despite the effectiveness of ERT in MPS VI patients, unmet needs still exist. Horovitz et al.  reported that early initiation of ERT may not fully prevent poor outcomes, including hearing loss, corneal clouding, skeletal, cardiologic, and nervous symptoms. In the present study, clinical symptoms including coarse face, joint contracture, snoring, and obstructive sleep apnea were improved after ERT; and urine GAG was decreased. In addition, one year of ERT did not prevent the progression of carpal tunnel syndrome and genu valgum in the patient.
In our patient, LVMI was remarkably decreased, but heart valve regurgitation did not improve despite ERT, which was similar to the cases of P1, P2, and P3 (Table 2). In a retrospective study of cardiac involvement of MPS VI in 44 patients aged from 0 to 42 years (mean 6.7 years) , the prevalence of LV hypertrophy was reported 53.3% in male and 27.3% in female. In the same study, LV remodeling was improved in three out of eight and LV hypertrophy was improved in four out of eleven after a mean follow-up of 5.9 years on ERT.
Interestingly, our patient was diagnosed with GH deficiency and MPS VI. To date, only one patient with MPS VI and GH deficiency has been reported . Whether GAG accumulation in the brain interferes with GH releasing hormone secretion from the hypothalamus is not known . In general, the short stature in MPS VI patients is due to abnormal GAG deposition, resulting in impaired cellular function in skeletal development. Growth plates are particularly sensitive to the accumulation of partially degraded GAGs such as dermatan sulfate and chondroitin sulfate, which subsequently leads to short bones and growth plate disorganization . Regarding the effectiveness of ERT on height in patients with MPS VI, several studies have shown partially positive results. Horovitz et al.  reported an average height gain of 3.1±1.2 cm/yr after early ERT. Decker et al.  reported that in a study of 56 MPS VI patients (age, 5-29 years), the mean height increased by 2.9 cm and 4.3 cm after 48 and 96 weeks of ERT, respectively. However, the long-term effect of GH treatments on growth is unknown, and only limited cases of GH therapy in MPS VI have been reported to date [13,14]. Cattoni et al.  reported an average increase in height velocity z-score of +4.23±2.9 and +4.55±0.96 after 6 and 12 months of GH treatment, respectively. Polgreen and Miller  reported that growth velocity increased from 2.3 cm/yr to 5.9 cm/yr after 1 year of GH treatment. In the present study, she gained a height of 7.5 cm/yr with combined ERT and GH therapy, a height velocity faster than that of healthy children (Fig. 2) . In this regard, the efficacy of the combination of ERT and GH therapy needs to be investigated in well-organized studies.
We describe a Korean patient with an MPS VI diagnosis and a novel missense mutation, c.1157C>T (p.Ser386Phe), in the
The authors declare that they do not have any conflicts of interest.
This study was supported by a 2022 research grant from Pusan National University Yangsan Hospital, Korea.
Conception and design: SY and CKC. Acquisition of data: SY, JL, MK, and JYY. Analysis and interpretation of data: SY, JL, MK, and JYY. Drafting the article: SY and CKC. Critical revision of the article: SY, CKC, and JYY. Final approval of the version to be published: all authors.
Comparison of clinical findings before and after enzyme replacement therapy (ERT)
|Variable||Before ERT||1 year after ERT|
|Body mass index z-score||0.88||–0.16|
|Urine GAG (mg/mmolCr)||55.8||15.4|
|6-minute walking test (m)||450||524|
|Pulmonary function test (%)|
|Valvular heart disease||Trivial MR
|Trivial MR and mild Thickening of posterior leaflet of mitral valve, trivial AR|
||62.1 (36.9-72.1)||42 (36.9-72.1)|
||52.4 (23.2-43.5)||29.1 (23.2-43.5)|
|Volume of organ
||477 (507.2-686.4)||624 (568.3-734.2)|
||83 (100-168)||93 (96-174)|
Values are presented as number only or number (reference range).
aReference range (10th-95th percentile) of LVM and LVMI was cited from article of Khoury et al. .
bThe volume of liver and spleen was measured by computed tomography scan.
GAG, glycosaminoglycan; FVC, forced vital capacity; FEV1, forced expiratory volume in one second; FEF25-75, forced expiratory flow at 25-75% of the pulmonary volume; MR, mitral regurgitation; AR, aortic regurgitation; LVM, left ventricular mass; LVMI, LVM index.
Genotype and clinical manifestations of mucopolysaccharidosis VI in Korea
|Chief complaint at initial presentation||Short stature||Corneal opacity||Coarse face, joint stiffness, kyphosis, growth retardation||Short stature, coarse face, corneal opacity, multiple joint stiffness|
|Age at diagnosis (yr)||6.5||4||2||24|
|Age at start of ERT (yr)||6.7||6||15.8||27|
|Enzyme activity||0.06 (RR>3.4 uM/hr)||0.1 (RR: 12-39 pmol/min mg protein)||8.1 (RR: 1.5-21 pmol/min mg protein)||28 (RR: 115-226 nmol/hr mg protein)|
|Urine GAG level at start of ERT||55.8 (RR<8)
(CPC unit/g Cr)
(CPC unit/g Cr)
(CPC unit/g Cr)
|6-12 Minutes of walking||6 min||12 min||12 min|
|Limitation of ROM||+||+||+||+|
|Edematous optic disc||–||–||–||+|
|Valvular heart disease||MR, AR||AS, AR, MS, MR, TR||AR, MS, MR, TR, PR||AS, MR|
|Restrictive lung disease||–||+||+||+|
|Joint contracture||+||Elbow, hip, knee||Hip, knee||Elbow, wrist, knee|
|Carpal tunnel syndrome||+||+||+||+|
|Spinal cord compression||–||+||+||+|
aP1, P2, and P3 were referred from the article of Wichajarn K et al. (J Korean Soc Inherit Metab Dis 2016;16:24-33) .
+, presented in case; –, not presented in case. ERT, enzyme replacement therapy; RR, reference range; GAG, glycosaminoglycan; ND, not done; ROM, range of motion; MR, mitral regurgitation; AR, aortic regurgitation; AS, aortic stenosis; MS, mitral stenosis; TR, tricuspid regurgitation; PR, pulmonaryr regurgitation; BMT, bone marrow transplantation.