1 INTRODUCTION

Metabolic cutis laxa is a rare, heterogeneous group of inherited skin and connective tissue disorders characterized by skin and connective tissue laxity. ALDH18A1 encodes Δ-Pyrroline-5-carboxylate synthase (P5CS), which is a central molecule in the interconversion of glutamate, ornithine, and proline (Pérez-Arellano et al., 2010). Deficiencies in P5CS enzymatic activity can result in skin laxity, microcephaly, cataracts, joint laxity, and hypotonia. Patients have been described as having a progeroid appearance associated with autosomal recessive inheritance and typically have severe phenotypes (Bicknell et al., 2008; Zampatti et al., 2012). In contrast, heterozygous pathogenic variants in the ALDH18A1 gene have been described in a small number of patients (Bhola et al., 2017; Fischer-Zirnsak et al., 2015; Kapoor et al., 2020; Koh et al., 2021). While there is some phenotypic heterogeneity, there are no reports of cervical spine pathology. We expand on the features of a previously reported patient with ALDH18A1 mutation (Fischer-Zirnsak et al., 2015) who was later found to have atlantoaxial instability after developing spinal cord compression following a fall from standing height. We review the relevant literature and suggest increased awareness of a potentially serious feature.

2 CLINICAL REPORT

A 10-year-old boy with a pathogenic variant in ALDH18A1 resulting in a phenotype consistent with a metabolic cutis laxa presented to our emergency department with weakness after falling backward from standing, striking his head on a bookshelf. Per the parental report, he was unresponsive for 3–5 min and confused thereafter. He reportedly did not move his arms and legs for 30 min before evaluation in the emergency department.

The patient's history is significant for a heterozygous pathogenic variant in ALDH18A1 with a substitution (c.413G>A, p.Arg138Gln) of arginine by glutamine at amino acid position 138 within the gamma-glutamyl kinase domain of P5CS. He was reported in a series of eight families (tab. 1, Family 8, Fischer-Zirnsak et al., 2015) and followed by two of the authors (A.E.L. and I.S.) for growth restriction, bilateral cataracts, congenital hip dysplasia, lax joints, aortic and pulmonary artery dilation, and recently, progressive motor decline. He had been treated with citrulline and proline replacement, given low plasma levels. He developed progressive motor decline over a 2-year period, requiring a walker for ambulation before his fall. The baseline exam before his accident was notable for weak volitional activation of his lower extremities, hyperreflexia, spasticity of lower extremities concerning upper motor neuron weakness, and rigidity and bradykinesia concerning extrapyramidal dysfunction.

Upon presentation to the hospital, he was hemodynamically stable with 3/5 strength in his upper extremities and 4/5 in his lower extremities with increased tone. The primary, secondary, and tertiary trauma surveys were otherwise negative. Computed tomography of the head and cervical spine demonstrated an age-indeterminant fracture of the dens. Following imaging results, he was placed in a cervical collar 6 h after his arrival. Magnetic resonance imaging of the cervical spine demonstrated: T2 hyperintense cord signal at the cervicomedullary junction; C1 with partial fusion of the C1 vertebra; the anterior position of lateral masses of C1 suggestive of posterior atlantooccipital subluxation; and suspected ligamentous injury between posterior elements of C1 and C2 (Figure 1). On repeated exams 12 h after arrival to the ED, strength decreased to 3/5 in his lower extremities. Due to his worsening exam, he was taken directly to the operating room for cervical spine fusion and decompression at C1, where he was found to have significant gross instability at the craniocervical junction and hypermobile spinal elements at C2. Motor-evoked potentials and somatosensory-evoked potentials were unchanged. Phenylephrine infusion was required intraoperatively to reach augmented blood pressure parameters to optimize spinal perfusion. He received packed red blood cells during the operation and prophylactic antibiosis.

He was admitted directly to the pediatric intensive care unit, where he remained on norepinephrine for 48 h to optimize spinal perfusion. His postoperative course was uncomplicated, and subsequent exams showed movement of all extremities, with greater strength in his right extremities (2/5 upper and 3/5 lower) versus his left (1/5 upper and 2/5 lower). Over the course of his 9-day hospitalization, strength improved to 4/5 in the right upper and lower extremities and 4/5 in the left lower extremities but remained 1/5 in the left upper extremity. Follow-up imaging showed intact hardware and alignment of the superior dens and C2 and redemonstrated ligamentous injury. He required extensive rehabilitation during a 2-month hospitalization. Fourteen months after his injury and with ongoing therapies, he can walk short distances unassisted, climb stairs with assistance, and requires a wheelchair for long distances.

3 DISCUSSION

Metabolic cutis laxa is a heterogeneous group of connective tissue disorders with broad-ranging clinical manifestations in most organ systems, including skin, cardiac, pulmonary, and neurologic systems. Our patient's phenotype also includes postnatal growth delay, bilateral cataracts, hip dislocation, joint hyperlaxity, osteopenia, and progressive motor decline. In addition to the eight patients (including this boy) described by Fischer-Zirnsak et al. (2015), there are two new patients (Table 1) with heterozygous ALDH18A1 variants in the literature but none with known cervical instability. ALDH18A1-related spastic paraplegia (SPG9A reflecting the dominant condition and SPG9B the recessive) has also been recently recognized (Coutelier et al., 2015; Kalmár et al., 2021). However, we have not included the unique family with spastic paraplegia in five individuals harboring a heterozygous mutation (c.755G>A, p.R252Q) in ALDH18A1, as the phenotype is distinct (Koh et al., 2021). We did not include patients with autosomal recessive ALDH18A1, although it is possible similar clinical manifestations could occur in these patients.

ALDH18A1 encodes Δ-P5CS. The clinical phenotype in P5CS deficiency is characterized by cutis laxa (thin skin with visible veins and wrinkles), microcephaly, bilateral subcapsular cataract(s), intellectual disability, joint laxity and hypotonia, structural brain abnormalities, progressive neurodegeneration, seizures, peripheral neuropathy, and dystonic movements in the hands and feet (Mohamed et al., 2011). P5CS is a bifunctional enzyme that catalyzes the reduction of glutamate to Δ¹-pyrroline-5-carboxylate (P5C), a central molecule in the interconversion of glutamate, ornithine, and proline (Mohamed et al., 2011). Decreased levels of plasma proline and the urea cycle intermediates (ornithine, citrulline, and arginine) are seen in some patients (Coutelier et al., 2015; Panza et al., 2016) including ours who was heterozygous for a de novo variant on the highly conserved amino acid Arg138 (c.413G>A; p.Arg138Gln). Fibroblasts from individuals with heterozygous variants on Arg138, including our patient, demonstrated altered sub-mitochondrial distribution and structure or composition of P5CS mutant complex and reduced P5CS enzymatic activity leading to a delayed proline accumulation (Fischer-Zirnsak et al., 2015).

Several pathophysiological explanations for the clinical findings in P5CS deficiency can be hypothesized (Mohamed et al., 2011; Pérez-Arellano et al., 2010; Zampatti et al., 2012). (1) The decreased bioavailability of proline possibly results in impaired synthesis of proteins with high proline content dependent on endogenous production; the cutaneous, vascular, cartilaginous, and bony features may be a result of deceased or structurally altered collagen or elastin in connective tissues. (2) Proline deficiency may cause impaired synthesis of brain polypeptides with otherwise neuroprotective functions that result in neurotransmitter dysregulation at the glutamatergic synapses, thus accounting for the neurological features. (3) Proline is postulated to function as an antioxidant, as a redox coupled with P5C, and as a regulatory factor in cell growth, cell death, ATP production, and immunomodulation (Karna et al., 2019). (4) In addition, decreased ornithine, an important intermediate of the urea cycle, results in deceased activity of the cycle and decreased synthesis of endogenous citrulline and arginine, thereby leading to hyperammonemia in fasting states; dietary arginine can temporarily correct the hyperammonemia. It is possible that mild but recurrent episodes of hyperammonemia contribute to the development of neurological deficits over time (Zhan & Stremmel, 2012). These episodes may lead to chronic nerve injury, resulting in hyperreflexia.

We hypothesize that our patient's metabolic disorder predisposed him to develop instability of his cervical spine and subsequently sustained severe injuries from an otherwise minor trauma. Ligamentous laxity resulting from this complex pathophysiology may underlie cervical spine pathology. It is possible hyperreflexia contributed to spinal injury as well, although hyperreflexia has been noted in this disorder in other patients without cervical pathology. Cervical spine injuries from non-penetrating trauma are rare in the pediatric population, occurring in approximately 1% of traumatic injuries. Only 19% of those injured require surgical intervention (Kim et al., 2020). Injuries sustained by falls from standing height are even less common (Schwartz et al., 1997), further highlighting our patient's increased predisposition for spinal injury.

Because of the high morbidity associated with spinal injuries, patients with conditions known to have higher rates of cervical spine anomalies may undergo routine screening, including Trisomy 21 (Myśliwiec et al., 2015; Stadler, 2022), mucopolysaccharidosis (Solanki et al., 2012), Loeys–Dietz syndrome (Prablek et al., 2022), and Ehlers–Danlos syndrome (Lohkamp et al., 2022). Due to the rarity of metabolic cutis laxa, there are no evidence-based treatment or management guidelines, and the prevalence of atlantoaxial instability is unknown. We recommend that metabolic cutis laxa patients undergo routine screening by history and physical exam and baseline cervical spine radiographs.

AUTHOR CONTRIBUTIONS

Conceptualization: Alexandra T. Lucas, Ryan W. Carroll, and Angela E. Lin. Writing—original draft: Alexandra T. Lucas, Andrew Cohen, Inderneel Sahai, Ryan W. Carroll, Angela E. Lin. Writing—review and editing: All authors.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.