Table 3 Comparison of initial symptoms reported in late-infantile and juvenile MLD

Artigalas et al. 2010 [9]

Brazil

29

22

4

1

• Gait abnormality or frequent falls: 72.7%

 • Neuropsychomotor development delay: 31.8%

• Behavioral abnormalities: 4.5%

• Cognitive deficit: 4.5%

• Cognitive deficit associated with walking alterations: 25%

• Cognitive deficit: 50%

• Behavioral and cognitive alterations: 75%

Bascou et al. 2020 [35]

Unclear

122

NR

NR

NR

Patients with onset before 3 years of age presented predominantly with gross motor involvement

Patients with onset between 6 and 16 years of age presented mainly with cognitive impairment

Bascou et al. 2017 [34]

USA

104

63^a

• Early-juvenile: 22^b

• Late-juvenile: 14^b

5^b

• Delayed achievement of gross motor milestones: 46.0%

• Abnormal gait: 28.6%

• Gross motor regression: 20.6%

• Early-juvenile MLD had similar initial symptoms to late-infantile MLD

• Some cases involved impairment of fine motor skills and language acquisition

• Late-juvenile MLD had mainly cognitive deficiencies

• Memory/attention/learning difficulties: 50%

• Changes in personality: 21.4%

Bindu et al. 2005 [38]

India

40

36

4

0

• Baseline delay in milestones followed by regression: 38.8% (14/36)

– Others developed regression after a period of normal development

• Independent walking attained before the onset of illness: 50% (18/36)

– Frequent falls as the initial symptom: 78% (14/18)

• Behavioral abnormalities such as attention deficits, hyperactivity, inappropriate laughter, and hyper-oral behavior: 100% (4/4)

• Learning problems and scholastic backwardness: 100% (4/4)

• Myoclonic jerks: 75% (3/4)

• Sluggish or absent deep tendon reflexes, indicating underlying neuropathy: 100% (4/4)

Carson et al. 2015 [86]

USA

90

58

29

3

Initial symptoms were mostly related to changes in gait

In late-juvenile MLD, the initial symptoms were changes in cognitive and behavioral function

Eichler et al. 2016 [81]

USA, France, Germany, and Colombia

23

14

6

3

Initial symptoms included:

• frequent falling or other walking problems

• regression of speech or motor skills

• behavioral abnormalities

Initial symptoms included:

• gait problems

• behavioral abnormalities

Fumagalli et al. 2021 [49]

Italy

45

22

19

Early-juvenile: 14

Late-juvenile: 5

4

• No independent walking: 40.9% (9/22)

• No independent sitting: 4.5% (1/22)

• Gait impairment (unsteadiness, frequent falls, and toe walking variably associated with musculoskeletal abnormalities such as foot deformities or retro-curved knees): 54.5% (12/22)

• Nystagmus: 4.5% (1/22)

• Strabismus: 9.1% (2/22)

Early-juvenile MLD

• Isolated gross motor impairment (tripping or falling, clumsiness, and poor balance): 28.6% (4/14)

• Isolated behavioral and/or cognitive regression: 35.7% (5/14)

• Decline of both cognitive and fine or gross motor skills: 35.7% (5/14)

• Seizures: 7.1% (1/14)

• Loss of bladder control: 35.7% (5/14)

• Late-juvenile MLD

• Isolated behavioral and cognitive regression, such as attention deficit, reduced school performance, social withdrawal, and loss of sphincter control: 100% (5/5)

Harrington et al. 2019 [53]

USA

32

plus eight siblings

16

16

0

• Problems with gross motor function (particularly in walking): 75.0% (12/16)

• Never learned to walk independently: 68.8% (11/16)

• Experienced symptoms relating to gross motor function by the time of diagnosis: 93.8% (15/16)

• Decline in cognitive function before diagnosis: 6.3% (1/16)

• Changes in cognitive function: 56.3% (9/16)

• Changes in social/behavioral function: 43.8% (7/16)

• Decline in gross motor function by the time of diagnosis (slowed movements, affected gait, and loss of balance): 56.3% (9/16)

Kehrer et al. 2014 [57]

Germany

59

23

36

0

None of the patients with late-infantile MLD had exclusively “non gross motor” symptoms as the first signs of disease (P values are for late-infantile vs. juvenile MLD)

• Gait disturbance: 70% (16/23); P = 0.9922

• Pain: 26% (6/23); P = 0.2447

• Abnormal movement patterns: 61% (14/23); P = 0.5011

• Impaired fine motor skills: 17% (4/23); P = 0.0011

• Restlessness/irritability: 17% (4/23); P = 0.3645

• Weakness: 43% (10/23); P = 0.5748

• Problems with concentration: 0% (0/23); P = 0.0001

• Behavioral problems: 13% (3/23); P = 0.0012

• Developmental regression in general: 61% (14/23); P = 0.5449

• Exclusively “non-gross-motor” symptoms as the first signs of disease: 17% (6/36)

• “Impaired fine motor skills”, “concentration problems”, and “behavioral problems”: 36% (13/36)

• Gait disturbance: 69% (25/36)

Pain: 14% (5/36)

• Abnormal movement patterns: 69% (25/36)

• Impaired fine motor skills: 61% (22/36)

• Restlessness/irritability: 28% (10/36)

• Weakness: 36% (13/36)

• Problems with concentration: 64% (23/36)

• Behavioral problems: 56% (20/36)

• Developmental regression in general: 53% (19/36)

Kehrer et al. 2021 [5]

Germany

97

35

56

• Early-juvenile: 18

• Late-juvenile: 38

6

• Motor symptoms only: 91% (32/35)

• Motor and cognitive symptoms: 9% (3/35)

Early-juvenile MLD

• Motor symptoms only: 61% (11/18)

• Motor and cognitive symptoms: 39% (7/18)

• Late-juvenile MLD

• Cognitive symptoms only: 61% (23/38)

• Motor symptoms only: 13% (5/38)

• Motor and cognitive symptoms: 26% (10/38)

Mahmood et al. 2010 [63]

USA

303 (SLR)

3 cases

98 (SLR)

3 cases

78 (SLR)

127 (SLR)

A total of 38 late-infantile cases had detailed clinical features provided

• Motor or gait abnormalities: 61%

Seizures: 39%

The first symptom was rapid progression in lower extremity muscle tone; all three siblings lost the ability to walk within days of each other

• Pooled SLR survival analysis

• Inattention and difficulties at school: 66%

• Gait difficulties: 26%

• Tremor or ataxia: 18%

• Neuropathy: 13%

• Seizures: 5%

Raina et al. 2019 [65]

India

12

4

8

0

Reported symptoms at presentation^b

• Motor impairment: 100% (4/4)

• Neurocognitive impairment: 100% (4/4)

• Language impairment: 100% (4/4)

• Seizures: 25% (1/4)

• Psychomotor regression: 75% (3/4)

• Bilateral spasticity: 100% (4/4)

• Areflexia: 50% (2/4)

Reported symptoms at presentation^b

• Motor impairment: 75% (6/8)

 • Neurocognitive impairment: 87.5% (7/8)

• Language impairment: 87.5% (7/8)

• Seizures: 12.5% (1/8)

 • Psychomotor regression: 0% (0/8)

• Gait difficulty: 63% (5/8)

• Extrapyramidal features (generalized dystonia): 38% (3/8)

• Ataxia: 25% (2/8)

Saeed et al. 2017 [24]

Saudi Arabia

14

12

2

NR

All presented with psychomotor regression of achieved developmental milestones (motor milestones regression, cognitive deterioration, and generalized spasticity)

Other clinical findings

• Optic atrophy: 100% (14/14)

• Convulsions: 14.25% (2/14)

• Small head size: 14.25% (2/14)

The two patients who received a diagnosis of juvenile MLD presented with ataxia and cognitive decline