Finnish Variant of Gelsolin Amyloidosis in a South Indian Family: Clinical, Genetic, Ophthalmological, and Histopathological Findings

Dear Editor,

Gelsolin amyloidosis (AGel) is a rare inherited disorder caused by an autosomal dominant mutation in GSN, which encodes the protein gelsolin.[1] It was first described by a Finnish ophthalmologist, Meretoja, in 1969.[2] Although most prevalent in Finland (~1000 carriers), cases are reported globally across diverse ancestries.[3,4] Symptoms develop in the 3^rd or 4^th decade, with corneal dystrophy, facial paresis, loose skin with reduced elasticity or cutis laxa, and cranial and peripheral neuropathies.[5,6] There can be autonomic dysfunction and cardiac conduction disorders. AGel is a potential mimic of motor neuron disease (MND) given its features of facial paresis, tongue atrophy and fasciculations, dysarthria, and dysphagia.[7] We present the clinical, genetic, ophthalmological, and histopathological features of a South Indian family with genetically confirmed AGel. The proband was initially diagnosed with Bulbar MND elsewhere. She [Figure 1; pedigree, II-3] is a 70-year-old woman from southern India who presented with a 10-year history of progressive, asymmetric facial weakness, which remained functionally nonsignificant until last 3 months, when she presented to us. During this period, she experienced speech difficulty, especially with labial sounds; challenges in eating due to poor lip closure; and drooling of saliva. She reported left-sided facial twitching, burning sensation in the eyes for 2 years, and occasional fullness of the left ear with tinnitus. Physical examination showed dermatochalasis, facial skin laxity [Figure 1a], bilateral corneal opacities, and flat feet. Neurological examination confirmed irregular twitching of the face and chin, severe asymmetric facial weakness, macroglossia, and tongue atrophy [Figure 1b] with fasciculations. Tongue and palatal movements were normal. The limb muscle tone and power were normal, and tendon reflexes were brisk. Evaluation by a speech–language pathologist revealed minimal flaccid dysarthria with mild oral phase dysphagia.

Figure 1.

(a) Picture of the proband showing cutis laxa. (b) Macroglossia and tongue atrophy. (c) Picture of the proband’s son showing facial weakness with decreased prominence of the right nasolabial fold. A three-generation pedigree is shown at the bottom left panel. The proband is indicated with an arrow. Sanger sequencing electropherograms of the c.487G>A variant found in GSN are shown on the bottom right panel

Her younger son [Figure 1; pedigree, III-3], aged 42 years, reported facial deviation to the left for 2 years and facial twitching. Neurological examination showed right-sided facial weakness [Figure 1c], tongue atrophy, and brisk tendon reflexes. The elder son [Figure 1; pedigree, III-2], aged 44 years, was asymptomatic with a normal physical examination. No other family members reported similar symptoms, and there was no known Finnish ancestry.

The proband’s muscle ultrasound showed modified Heckmatt grade 1 muscle echotexture and fasciculations in the genioglossus. Electromyography of the tongue, paraspinal, and limb muscles revealed a neurogenic process. Nerve conductions of the facial nerve showed absent potential from the right side and mild motor sensory axonopathy [Supplementary Tables 1 and 2]. Pure tone audiometry revealed bilateral sensorineural hearing loss. Cervical spine magnetic resonance imaging did not reveal significant pathology.

Supplementary Table 1.

Electromyography findings summary

Muscle		Side		Insertional activity		Fibrillations/fasciculations		Positive sharp wave		MUAP		Duration		Interference pattern
Abductor pollicis brevis		Right		Normal		Fasciculations		Present		Normal		Normal		Complete
Hypoglossal		Right		Normal		Absent		Absent		Normal		Normal		Nearly complete
Hypoglossal		Left		Normal		Fasciculations		Absent		Normal		Normal		Complete
Tibialis anterior		Right		Normal		Fasciculations- doublets and triplets		Present		Normal		Normal		Incomplete
Opponens pollicis		Right		Normal		Fasciculations		Present		Polyphasic		Normal		Complete
Paraspinal		Right		Normal		Fasciculations- doublets and triplets		Present		Normal		Normal		Incomplete

MUAP: Motor unit action potential

Supplementary Table 2.

Nerve conduction study findings summary

MNCV		Site/segment		Latency (milliseconds)		Amplitude (millivolts)		Duration (milliseconds)		Area (mVms)		Distance (millimetres)		NCV (meters/second)
Median R		Wrist-Abductor pollicis brevis		4.3		3.9		6.4		12.8
		Elbow-Wrist		8.0		4.4		6.9		15.8		220		59.7
CPN R		Ankle-Extensor digitorum brevis		2.4		2.0		7.2		7.9
		Below fibular head-Ankle		10.1		2.0		8.0		5.2		340		44.2
		Above fibular head-Below fibular head		12.1		2.0		8.3		5.5		100		49.0
PTN R		Medial malleolus-abductor hallucis brevis		5.2		1.2		7.0		5.5		-		-
		Popliteal fossa-medial malleolus		16.0		0.6		6.6		5.2		360		33.4
Facial R		Orbicularis occuli		1.3		0.7		47.4		138.7		-		-
Facial R		Below earlobe-nasalis		-		-		-		-		-		-
Facial L		Below earlobe-nasalis		3.6		0.7		7.1		6.8		-		-
Trapezius R		-		2.6		4.5		14.2		39.8		-		-
Median L		Wrist-Abductor pollicis brevis		4.5		7.1		5.5		24.7		210		60.2
		Elbow-wrist		8.0		6.6		5.7		23.7		-		-
Median L		Wrist-Abductor pollicis brevis		4.3		7.1		7.3		29.7		-		-
CPN L		Ankle-Extensor digitorum brevis		3.7		6.3		4.8		11.8		-		-
		Below fibular head-ankle		10.4		5.8		4.9		15.2		320		47.7
		Above fibular head-below fibular head		11.7		5.5		5.8		14.4		70		53.2
SNCV
Median R		Wrist-digit 2		3.2		21.1		3.6		32.1		130		40.2
Ulnar R		Wrist-digit 5		2.7		19.9		2.9		42.7		110		40.0
Sural R		Lateral malleolus		3.6		14.9		2.6		12.9		120		33.6
Median L		Wrist-digit 2		3.3		29.2		2.4		58.5		110		40.1
Ulnar L		Wrist-digit 5		2.5		21.6		2.4		58.5		110		40.1
Sural L		Lateral malleolus		2.7		10.3		2.0		43.8		110		41.4

MNCV: Motor nerve conduction velocity, mVms: millivolt: milliseconds, NCV: Nerve conduction velocity, R: Right, CPN: Common peroneal nerve, PTN: Posterior tibial nerve, L: Left, SNCV: Sensory nerve conduction velocity

Whole-exome with mitochondrial genome sequencing was performed. Genetic variants were identified using the Genome Analysis Toolkit Best Practices pipeline for germline variant discovery. The detected variants were interpreted and classified according to the American College of Medical Genetics and Genomics guidelines. A heterozygous missense pathogenic variant in exon 5 of GSN, namely NM_198252.3:c.487G>A, that results in the amino acid substitution of asparagine for aspartic acid at codon 163 (p.Asp163Asn; NP_937895.1) was detected. Variant confirmation and segregation analysis by Sanger sequencing on DNA in the proband and her sons revealed the presence of the same variant in the affected son in a heterozygous state.

Ophthalmological assessment showed corneal stromal opacity [Figure 2a]. On slit-lamp examination with the retro illumination technique, type 2 lattice corneal dystrophy (LCD) was noted, with radially oriented refractile lines more in the peripheral cornea [Figure 2b] with relative central sparing and central amorphous dots. On optical coherence tomography, both eyes showed temporal pallor with temporal borderline retinal nerve fiber layer thinning and central macular ganglion cell layer thinning [Figure 2c, 2d]. In the right eye, vitreomacular traction with cystic changes in the inner nuclear layer was identified. A limited ophthalmic assessment of the proband’s affected son showed type 2 LCD [Figure 2e] and a normal fundus.

Figure 2.

(a) Corneal stromal opacity. (b) Proband left eye–slit lamp examination with the retro illumination technique showing lattice corneal dystrophy. (c and d) Temporal pallor with temporal borderline retinal nerve fiber layer thinning and central macular ganglion cell layer thinning on optical coherence tomography (OCT). (e) Slit lamp examination of the proband’s son showing lattice corneal dystrophy

A forearm skin punch biopsy showed epidermal thinning and Congo red-positive eosinophilic material in the papillary dermis with apple-green birefringence under polarized light, consistent with amyloid deposition [Figure 3].

Figure 3.

(a and b) A band of pink amorphous material (amyloid) in the papillary dermis indicated by black arrows (H and E, ×10, ×20), (c) Pale blue appearance of amyloid compared with the blue color of the dermal collagen underneath indicated by yellow arrows (Masson trichrome, ×10). (d) Congo red stain (×20). (e and f) Amyloid deposit in the dermis exhibiting “apple-green” birefringence under polarizing light (Congo red stain under polarizer, ×20)

This is the second report of a family with AGel from India and the first genetically confirmed case series. The previous family involved eight affected members, where the proband presented with with AGel in his 6^th decade with facial twitching, bifacial weakness, and LCD.[8]

AGel is commonly associated with the c.487G>A variant in GSN (ClinVar ID: 16180), resulting in the amino acid substitution p.Asp163Asn (p.D163N), which was also identified in our patient. This variant was first shown to co-segregate with the disease in three large Finnish families with AGel.[9] A second, less common allelic variant, namely c.487G>T (referred to as the Danish variant), results in the substitution of asparagine with tyrosine (ClinVar ID: 16181). Several individual reports of novel pathogenic variants in GSN have been published, expanding the AGel mutational spectrum. Although AGel typically presents with a core set of features such as LCD, facial palsy, and cutis laxa, phenotypic variability is noted. A summary of genetically confirmed AGel cases published in last 6 years is presented in Supplementary Table 3.

Supplementary Table 3.

Clinical and genetic summary of Gelsolin amyloidosis cases reported in last six years (from 2020 to July 2025)

Study, Country		This report		Sevilla et al., 2025, Spain[1]		Liang et al., 2025, China[2]		Abreu et al., 2024, Brazil[3]		Park et al., 2022, Korea[4]		Cheong et al., 2021, Korea[5]		Potrč et al., 2021, Slovenia[6]		Macias et al., 2020, Mexico[7]
Mutation		c.487G>A		c.1613T>C p.Leu538Pro		c.2245G>C p.Asp749His		c.640G>A p.Asp214Asn		c.640G>T p.Asp214Tyr		c.640G>T p.Asp214Tyr		c.1738G>A p.Glu580Lys		c.1631T>G transversion p.Met544Arg
No. of patients		2 individuals, Proband (Mother) and Son		10 individuals from two generations		1 girl		3 sisters		2 unrelated women		13 individuals from three unrelated families		6 individuals from two generations		5 individuals from three generations
Age at examination		70 and 42 years		Mean (available for 9 subjects) 62.44 years		11 years		Range 50–53 years		58 and 60 years		Median 73 years		Mean 59.33 years		Mean 53.8 years
Ocular findings		Corneal lattice dystrophy, optic neuropathy		Corneal lattice dystrophy		-		Corneal lattice dystrophy, progressive bilateral ptosis, ocular discomfort, dry eye syndrome, and ectropion		Corneal lattice dystrophy		Corneal lattice dystrophy		Corneal lattice dystrophy, optic neuropathy, cataract, open-angle glaucoma		Corneal lattice dystrophy
Dermatological findings		Cutis laxa		-		-		Cutis laxa		Cutis laxa		Cutis laxa		Cutis laxa		Cutis laxa
Neurological findings		Facial palsy, facial dyskinesia, macroglossia, tongue atrophy, fasciculations, and brisk Tendon reflexes		Carpal tunnel syndrome, Cervical spinal stenosis		-		Facial palsy, ataxia, peripheral neuropathy		Bilateral facial diplegia, Myokymia, Tongue atrophy, Dysarthria		Facial palsy, Dysarthria, Dysphagia, Carpal tunnel syndrome		Brain calcifications, sensory ataxia, carpal tunnel syndrome, white matter lesions, torticollis, tremor with sensory tic, blepharospasm, oromandibular dystonia		Paraesthesia, Numbness in extremities, carpal tunnel syndrome
Cardiac/renal involvement		None		Diastolic dysfunction, Atrioventricular and intraventricular conduction disorders, High prevalence of pacemaker use, pericardial effusion		Nephrotic syndrome		-		-		-		Arrhythmia, urolithiasis, renal cysts		cardiac valvulopathy, ischemic heart disease, and arrhythmia

AGel mimics bulbar MND, but it is distinguished by a characteristic triad of ophthalmological, neurological, and dermatological symptoms. AGel patients typically have long-standing illness, unlike MND, which progresses rapidly, with death occurring within 2–3 years due to respiratory failure. Natural history studies of AGel in the Finnish population indicate no significant impact on survival until, at least, 75 years of age, although the disease carries a significant burden due to multisystem involvement and invasive interventions during the lifetime of a patient.[10] Survival and disease burden in non-Finnish populations remain poorly understood.

This case emphasizes the need for high clinical suspicion in patients presenting with the characteristic triad to prevent the misdiagnosis of life-limiting conditions, such as MND, and to consider AGel as a differential diagnosis of LCD and facial paresis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.

F Wave		Motor latency (milliseconds)		F-Motor latency (milliseconds)		F minimum latency (milliseconds)		F maximum latency (milliseconds)		F/M amplitude		F %
Median right		4.5		24.7		29.2		32.1		0.23		93
CPN right		3.2		46.8		50.0		51.1		0.15		62
PTN right		5.3		50.7		55.9		59.9		0.4		100
Median left		4.2		22.6		26.8		29.1		0.07		100
PTN left		3.9		50.4		54.3		56.8		0.02		87