FIC Domain Protein Adenylyltransferase (FICD)‐Related Complex Hereditary Spastic Paraplegia with Diabetes Mellitus

Biallelic variants in FICD have been linked to 2 distinct clinical phenotypes: slowly progressive motor neuron disease and infancy‐onset diabetes mellitus with severe neurodevelopmental delay. ¹ , ² Both phenotypes are associated with disruptions in the deAMPylase activity of FICD, leading to abnormal AMPylated Binding immunoglobulin protein (BiP) accumulation. ¹ , ² This imbalance may disrupt protein homeostasis by overwhelming the Endoplasmic reticulums (ER) folding capacity due to inactive BiP.

We expand the clinical spectrum of FICD‐related disease by identifying biallelic FICD variants in 2 families with complicated hereditary spastic paraplegia (cHSP) and diabetes mellitus, merging 2 previously distinct phenotypes (Table S1). Exome sequencing from 2 unrelated families revealed variants affecting the same key residue, Arg374, ³ located at the catalytic core motif of the enzyme crucial for deAMPylase function. ⁴ Family 1, from Serbia, had a recurrent homozygous variant, p.Arg374His, in 2 siblings, whereas Family 2, from Saudi Arabia, harbored a novel homozygous variant, p.Arg374Cys (Fig. 1). The variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG)/AMP guidelines (Table S2). ⁵ , ⁶ A founder effect was reported for Arg374His ¹ ; however, the haplotype reported was absent in Family 1, suggesting an independent mutation. Variants p.Arg374His and p.Arg374Cys lie in a CpG site, possibly a hot spot for methylation‐related mutations. [Correction added on 28 March 2025, after first online publication: the sentence has been changed from ‘Variants p.Arg374His and p.Arg373Cys lie in a CpG site’ to ‘Variants p.Arg374His and p.Arg374Cys lie in a CpG site’.]

FIG. 1.

Identification of biallelic variants in FICD in 2 families with cHSP (complicated hereditary spastic paraplegia) and diabetes. (A) Pedigrees of a Serbian and a Saudi Arabian family showing segregation of FICD variants with the disease. Affected individuals from Family 1 and Family 2 are homozygous for the variants Arg374His and Arg374Cys, respectively. (B) Diagram of the FICD protein showing main domains and the locations of the variants. Pathogenic variants leading to cHSP with or without diabetes are in red, and the pathogenic variant associated with infantile‐onset diabetes is in blue. All variants target the critical catalytic core motif of the protein, which is highly conserved across species. Figure format was adapted from Rebelo et al. ¹ [Correction added on 28 March 2025, after first online publication: Figure 1 has been updated]

In the first family, 2 siblings with cHSP and diabetes mellitus were born to healthy parents in northern Serbia. The brother exhibited lower‐limb spasticity by age 6. At age 25, he was diagnosed with diabetes mellitus that was treated with oral therapy for 5 years and later had to be put on low‐dose insulin therapy that led to better glucose control. Specific autoantibody testing for diabetes mellitus type 1 was not performed. At 46, he reported finger tingling and urinary urgency. Test showed bilateral amaurosis, mild hypoacusis, hypophonia, brisk palatal reflex, and a high‐arched palate. Upper‐limb findings included mild distal muscle atrophy, bilaterally brisk reflexes, and a positive Hoffman's sign. Additional findings included kyphoscoliosis, severe lower‐limb atrophy, spastic paraplegia, brisk reflexes, and a bilateral Babinski sign. Vibration sensitivity was reduced to the knees. Brain magnetic resonance imaging (MRI) at 33 showed moderate white matter reduction and posterior internal capsule gliosis from hypoxic–ischemic encephalopathy. Similar abnormalities of the posterior limb of the internal capsule have been observed in Ectonucleoside Triphosphate Diphosphohydrolase 1 (ENTPD1)‐related HSP, indicating a possible shared pathophysiological mechanism. ⁷ His sister exhibited walking difficulties by age 5 and at 27 was diagnosed with diabetes and treated with insulin. Specific autoantibody testing for diabetes was not performed. At 42, exam findings included a brisk palatal reflex and high‐arched palate, and mild distal atrophy, brisk reflexes, and positive Hoffman's sign in the upper limbs, and mild dysmetria, kyphoscoliosis, global atrophy, pes equinovarus, severe spastic paraplegia, brisk reflexes, and bilateral Babinski sign in the lower limbs. She could walk only a few meters with support, exhibiting a spastic‐paraparetic gait with a peroneal component and reduced vibration sensation to the dorsum of her feet.

In the second family, 2 sisters with progressive HSP and diabetes (one prediabetic) were born to consanguineous parents from southern Saudi Arabia. The older sister, started tip‐toe walking at 18 months, later developing urge incontinence, but no sensory, bulbar symptoms, or cognitive decline. Recently, she was diagnosed with diabetes mellitus. She was tested negative for anti‐GAD65 antibodies, and autoimmune etiology was excluded. At 11, she is wheelchair dependent with distal upper‐limb atrophy, mild weakness, and normal deep tendon reflexes. Her lower limbs exhibit talipes equinovarus, atrophy, scissoring hips, severe spastic paraparesis, brisky reflexes, positive Babinski sign, and normal sensation. MRI showed mild cerebral, cerebellar, and thoracic atrophy. The younger sister, 6 years old, had motor delay and tip‐toe walking. She currently experiences walking difficulties, no incontinence, normal cognition, and prediabetic status. Her lower limbs exhibited mild to moderate spastic paraparesis, increased distal muscle tone brisk tendon Achilles reflexes.

The identification of the p.Arg374His and p.Arg374Cys variants highlights the importance of the Arg374 residue in the catalytic activity of FICD, contributing to the neurological and metabolic abnormalities. Previously identified variant p.Arg371Ser, also located in the catalytic motif, caused infantile diabetes and neurodevelopmental delay. ² FICD regulates BiP, a key stress–response pathway for protein homeostasis in the ER. ³ , ⁸ The coexistence of motor neuron disease and diabetes in these patients suggests a broader range of neurological and metabolic effect of FICD dysfunction. These features may manifest together or independently, reflecting the heterogeneity of the condition and the underlying mutations. It is possible that diabetes could be a late‐onset complication in HSP. Similarly, spasticity might develop later in life in patients currently diagnosed with diabetes, because they are still young. It is also possible that the 2 conditions could occur by chance. Because diabetes is rare before age 30 and all 4 of our patients have it in some form, it is highly unlikely that this is a random association.

The identification of overlapping phenotypes in our patients with both cHSP and diabetes mellitus provides new insights into the pathophysiology of FICD‐related disorders, suggesting these phenotypes may represent a continuous clinical spectrum rather than entirely distinct entities. Understanding the complex biology of FICD and its role in disease is crucial for developing effective treatment strategies for patients with these rare genetic conditions.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Clinical and diagnostical evaluation: A. Recruitment, B. Evaluation; (3) Manuscript: A. Writing of the first draft, B. Review and critique.

A.P.R.: 1A, 1B, 1C, 3A, 3B

A.S.A.: 2A, 2B, 3B

A.A.H.: 2A, 2B, 3B

V.V.: 2A, 2B, 3B

S.A.: 2A, 2B, 3B

M.B.: 2A, 2B, 3B

Z.S.: 2A, 2B, 3B

S.Z.: 1A, 1B, 1C, 3B

A.A.‐S.: 1A, 1B, 1C, 2B, 3B

S.P.: 1A, 1B, 1C, 2B, 3B

Disclosures

Ethical Compliance Statement: Study participants provided written informed consent under an institutional review board (IRB)–approved research protocol (study number: 20070270, titled “Genetics of Hereditary Spastic Paraplegia”). We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This research was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health under award number 5R01NS072248 and 5R01NS105755‐03 (to S.Z.). The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Table S1. Clinical characteristics of FICD patients.

Table S2. ACMG pathogenic criteria met for novel FICD variant, Arg374Cys.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.